ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

Adoptive T cell transfer for tumor immunotherapy

Adoptive transfer of allogeneic hematopoietic stem cells (HSC) is an established treatment for hematological malignancies. Donor T cells are responsible for mediating the graft-versus- leukemia effect, but this is associated with graft-versus-host disease in up to 50% of transplant recipients. One of the most exciting applications of TCR gene transfer is the ability to generate autologous T cells that recognize leukemia or tumor antigens (Figure 1). There are a number of tumor associated antigens (TAA) that are being evaluated as targets for the immunotherapy of malignancies. However, while they are over-expressed on tumors, they are also expressed on normal tissues, albeit at low levels. Autologous T cells which naturally recognize tumor antigens with high affinity are subject to tolerance mechanisms such as deletion or anergy. Hence, although autologous T cell responses against tumor antigens can be detected in patients with malignancies, they are generally of low avidity. Since it has been shown that the transduced T cell population demonstrates the same functional avidity as the original parent T cell from which the TCR genes are cloned, one of the advantages of TCR gene therapy is that a high avidity TCR can be selected for transfer into target T cells. There are several methods by which high avidity cytotoxic T lymphocytes (CTL) specific for TAAs can be generated. Immunization of HLA transgenic mice, the allo-restricted approach, in vitro mutagenesis of TCRs, and in vitro selection using phage display have been used to generate TCRs with increased peptide/MHC binding affinity.

Figure 1. TCR gene transfer.
(i) A T cell bearing the appropriate TCR is identified, (ii) the alpha and beta TCR chains genes are isolated and cloned into a retroviral vector, (iii) the vector is used to transfect a packaging cell line which produces viral particles containing the genes of interest: (iv). (v) Target T cells are transduced with the recombinant viral particles; (vi) when the genes integrate into the host DNA the target cells express the desired TCR.

2008-2-en-King-et-al-Figure-1.jpg


Transduced T cells have been shown to contribute to tumor clearance in murine models , and the first clinical trial of TCR gene transfer was recently reported. Retroviral gene transfer was used to transduce peripheral blood lymphocytes taken from patients with melanoma, with the genes encoding the α and β chains of a TCR with specificity for a MART 1 peptide presented by HLA-A*0201. The 17 patients in the gene transfer study were lymphodepleted prior to receiving autologous T cells transduced with the MART-1 TCR. The engineered T cells persisted in 15 patients, and the two patients with the highest levels of circulating anti-melanoma T cells showed objective regression of metastatic lesions and remained in remission 18 months after treatment. The results of this study prove that retroviral TCR gene transfer can be used to confer anti-tumor specificity upon a large number of autologous T cells, and that these T cells can engraft in patients and persist at high levels long term.

TCR gene transfer to generate anti viral T cells

A further application for TCR gene transfer is to generate virus-specific T cells for the treatment of immunosuppressed patients who have undergone HSC transplantation. After GvHD, post transplant viral infection is the next major cause of morbidity and mortality in transplant recipients. Adoptive T cell transfer has been shown to be an effective treatment for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection in transplant recipients. Donor-derived CMV specific CD8 T cells which had been expanded in vitro were then infused into HSC transplant recipients with good effect. Similarly, donor-derived EBV specific T cell lines have been used to treat EBV related post-transplant proliferative disease. However, the major limitation of this strategy is that it is not possible to generate virus-specific CTL from all HSC donors using in vitro expansion techniques. TCR gene transfer has the ability to overcome this obstacle and confer upon donor T cells TCR specificities that are not present in the endogenous donor repertoire. This technique also has the advantage of generating large numbers of virus-specific CTL far more rapidly than standard in vitro expansion approaches, which would be of clear benefit in a clinical scenario where a patient presents acutely with significant morbidity. While clinical trial data is still pending, this strategy has great potential for the treatment of viral infections in HSC recipients.

Augmenting TCR gene transfer

In recent years, several groups have explored the means by which TCR gene transfer can be optimized. Modern vector designs aim to increase exogenous TCR expression on target cells by combining α and β chains in a single vector linked by viral self cleaving 2A sequences, rather than internal ribosome entry sites. Codon optimization of TCR gene sequences has also been shown to result in increased TCR expression in human CD8+ T cells, and increased antigen-specific IFNγ release.

In parallel with these vector modifications, recent research efforts have been directed towards increasing the preferential pairing of exogenous α and β chains with each other. It has been demonstrated that exogenous TCRs are able to mispair with endogenous TCR chains (Figure 2). Any mispairing may reduce the expression density and hence the efficacy of the desired TCR, since the density of TCR expression on the cell surface has been shown to correlate with avidity. A number of strategies have recently been employed to address this issue. TCRs have been engineered to include an additional cysteine residue in the constant regions of the α and β chains, resulting in the formation of a second disulphide bond between them. T cells transduced with cysteine-modified receptors showed increased tetramer binding, secreted more cytokine, and showed increased antigen specific lysis when co-cultured with specific tumor cell lines, compared with T cells expressing wild type TCR. Hybrid TCRs have also been designed to incorporate murine constant regions and human variable regions. These hybrid TCRs show reduced mispairing with fully human TCRs when introduced into human T cells, combined with superior cell surface expression and biological activity. However, there is a possibility that a human host will mount an immune response against the murine component of such a TCR. In the same way that murine monoclonal antibodies have become increasingly humanized for clinical use, it is likely that murinization of the TCR constant region will be minimized to reduce its immunogenicity, if this strategy is to be used in a clinical setting.

2008-2-en-King-et-al-Figure-2.jpg

Figure 2: exogenous and endogenous TCR chains compete for CD3 molecules for surface expression, and can mispair to form mixed dimers of unknown specificity. TCR α and β chains must form a complex with the ζ,δ,ε and γ CD3 chains in order for the TCR to be expressed on the cell surface. Following retroviral TCR gene transfer, there is competition between the endogenous TCR (A) and the exogenous TCR (B) for CD3. Increasing the availability of CD3 chains could increase the density of expression, and hence functional avidity, of the exogenous TCR. C: mispairing of endogenous and exogenous TCR chains leads to mixed dimer formation. These TCR have the potential to be autoreactive, and also reduce the CD3 available for expression of the desired TCR (B).


Strategies such as murinization of constant domains and cysteine modification of TCR chains reduce mispairing and increase the "strength" of a TCR. Recent data has shown that "strong" TCRs are expressed at high levels following retroviral gene transfer, whereas "weak" TCRs are poorly expressed because they compete poorly against the endogenous TCR repertoire for CD3 molecules. Research is ongoing into whether there are specific amino acid sequences in the TCR constant domain that contribute towards "strength." An alternative strategy that is currently being investigated is the cotransduction of TCR along with the genes encoding the CD3 complex. Endogenous and exogenous TCR chains are in competition for a limited pool of CD3 molecules, and exogenous TCR chains are likely to be present in excess, since their production is under the control of a retroviral promoter. The expectation would be that cotransducing with both TCR and CD3 molecules would increase the availability of CD3 molecules, which would have a more profound effect on expression of the exogenous TCR whose α and β chains are present in excess. 

Safety concerns

Although there is no evidence of off-target toxicity in murine models to date, it has been demonstrated that exogenous TCR are able to mispair with endogenous TCR chains, resulting in the expression of TCRs that have not undergone thymic education. These TCR, with unpredictable specificities, have the potential to be autoreactive. The strategies described above have been employed to both reduce mispairing and to increase expression of the desired TCR. Research is ongoing into alternative means by which the risk of mispairing may be reduced. It has recently been shown that TCR α and β chains which have each been linked to a CD3ζ chain did not mispair with endogenous TCR chains in a Jurkat T cell model. Since γδ TCR chains cannot mispair with αβ TCR chains, transferring αβ TCR chains into γδ T cells should not result in any mispairing, and has previously been shown to result in the expression of exogenous αβ TCR which produce cytokine and lyse target cells in an antigen-specific manner. Transduction of viral-specific T cells is a strategy by which the potential number of mixed dimers can be reduced; since anti viral responses consist of T cells with a restricted TCR repertoire. An alternative approach would be to transduce HSC with TCR genes. In vitro generation of mature, antigen-specific T cells by TCR gene transfer into thymus or cord-derived HSC has recently been reported. Allelic exclusion of the endogenous TCR β chain meant that mixed dimer formation was reduced, but not entirely avoided due to some endogenous α chain expression. However, while the risk of transformation of mature T cells is low, the risk in HSC may be higher, making this a less appealing strategy. In a clinical trial of X linked severe combined immunodeficiency disease, 4 children treated with HSC retrovirally transduced with the common γ chain developed T lymphoproliferative disorders. This was later found to be secondary to retroviral insertion into the LMO-2 oncogene intron on chromosome 11, with subsequent upregulation. Although there is no evidence to date of transformation of mature T cells with retroviral vectors, the use of lentiviral vectors is also being investigated, since it has been shown that lentiviral vectors insert near promoters at a lower frequency.

While there is a concern that low avidity, TAA specific CTL from the autologous repertoire may not be efficacious, high avidity, self-reactive CTL may pose the opposite problem. The majority of targets for tumor immunotherapy are over-expressed self proteins, and therefore there is a risk that targeting TAA may result in autoimmune damage. In murine models and in clinical trials it has been demonstrated that the successful induction of CTL responses against melanoma TAAs (such as melan A or gp100) has been associated with the development of vitiligo. T cell therapies targeting TAAs with a more ubiquitous distribution have not been studied in the same detail as yet, although it has been shown that high avidity p53 specific CTLs (generated in p53-/- transgenic mice) can provide tumor protection without causing autoimmune damage in mice. A moderately high affinity TCR was used in the TCR gene therapy trial, and work is now ongoing by the same group to test a higher avidity TCR. It remains to be seen whether any morbidity resulting from autoimmune disease outweighs the associated anti tumor benefit. A balance needs to be struck between TAA specific CTL which are of high enough avidity to mediate tumor killing, but which do not cause significant autoimmune damage to healthy tissue. It is likely that a large discrepancy between the expression level of the target antigen on tumor tissue compared to that on normal tissue will be an important factor in this regard, as will the pattern of distribution of the TAA in normal tissue. 

Conclusion

Although TCR gene transfer holds promise, there may yet be obstacles to overcome with respect to either the safety or the efficacy of this strategy. While mispairing of endogenous and exogenous TCR chains may result in off target toxicity, high avidity CTL may cause on target toxicity by attacking normal tissues that express low levels of the target antigen. However, recent clinical trial data has demonstrated that TCR gene transfer is an effective means by which a defined population of antigen specific T cells can be generated which persist following adoptive transfer into patients. Research is ongoing to address the safety issues and to improve the expression of retrovirally introduced TCRs. Furthermore, while the adoptive transfer of antigen specific regulatory cells has been less well explored to date, this warrants further investigation as there are a number of potential clinical applications for such a strategy. Although unanswered questions remain, it is evident that TCR gene transfer holds clear promise for the treatment of malignancies and viral infections and may have potential to treat unwanted immunopathology in the future. 

References

1. Stanislawski T, Voss RH, Lotz C, et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol. 2001;2:962-970.

2. Dembic Z, Haas W, Weiss S, et al. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature. 1986;320:232-238.

3. Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol. 1999;163:507-513.

4. Kessels HW, de Visser KE, Kruisbeek AM, Schumacher TN. Circumventing T-cell tolerance to tumour antigens. Biologicals. 2001;29:277-283.

5. Sadovnikova E, Jopling LA, Soo KS, Stauss HJ. Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules. Eur J Immunol. 1998;28:193-200.

6. Sadovnikova E, Stauss HJ. Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc Natl Acad Sci U S A. 1996;93:13114-13118.

7. Oka Y, Elisseeva OA, Tsuboi A, et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. Immunogenetics. 2000;51:99-107.

8. Rubinstein MP, Kadima AN, Salem ML, et al. Transfer of TCR genes into mature T cells is accompanied by the maintenance of parental T cell avidity. J Immunol. 2003;170:1209-1217.

9. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850-854.

10. Gao L, Bellantuono I, Elsasser A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198-2203.

11. Xue SA, Gao L, Hart D, et al. Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells. Blood. 2005;106:3062-3067.

12. Kessels HW, Wolkers MC, van DB, van d, V, Schumacher TN. Immunotherapy through TCR gene transfer. Nat Immunol. 2001;2: 957-961.

13. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126-129.

14. Peggs KS, Verfuerth S, Pizzey A, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362:1375-1377.

15. Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038-1044.

16. Heslop HE, Ng CY, Li C, et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996;2:551-555.

17. Haque T, Wilkie GM, Taylor C, et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360:436-442.

18. Szymczak AL, Workman CJ, Wang Y, et al. Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat Biotechnol. 2004;22:589-594.

19. Scholten KB, Kramer D, Kueter EW, et al. Codon modification of T cell receptors allows enhanced functional expression in transgenic human T cells. Clin Immunol. 2006;119:135-145.

20. Thomas S, Xue SA, Cesco-Gaspere M, et al. Targeting the Wilms tumor antigen 1 by TCR gene transfer: TCR variants improve tetramer binding but not the function of gene modified human T cells. J Immunol. 2007;179:5803-5810.

21. Hofmann M, Radsak M, Rechtsteiner G, et al. T cell avidity determines the level of CTL activation. Eur J Immunol. 2004;34:1798-1806.

22. Heemskerk MH, Hagedoorn RS, van der Hoorn MA, et al. Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex. Blood. 2007;109:235-243.

23. Cohen CJ, Zhao Y, Zheng Z, Rosenberg SA, Morgan RA. Enhanced Antitumor Activity of Murine-Human Hybrid T-Cell Receptor (TCR) in Human Lymphocytes Is Associated with Improved Pairing and TCR/CD3 Stability. Cancer Res. 2006;66:8878-8886.

24. Hart DP, Xue SA, Thomas S, et al. Retroviral transfer of a dominant TCR prevents surface expression of a large proportion of the endogenous TCR repertoire in human T cells. Gene Ther. 2008;15:625-631.

25. Sebestyen Z, Schooten E, Sals T, et al. Human TCR That Incorporate CD3{zeta} Induce Highly Preferred Pairing between TCR{alpha} and {beta} Chains following Gene Transfer. J Immunol. 2008;180:7736-7746.

26. Van der Veken, LT, Hagedoorn RS, van Loenen MM, Willemze R, Falkenburg JH, Heemskerk MH. Alphabeta T-cell receptor engineered gammadelta T cells mediate effective antileukemic reactivity. Cancer Res. 2006;66:3331-3337.

27. Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH. Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med. 2004;199:885-894.

28. van Lent AU, Nagasawa M, van Loenen MM, et al. Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors. J Immunol. 2007;179:4959-4968.

29. Zhao Y, Parkhurst MR, Zheng Z, et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 2007;67:2425-2429.

30. Recchia A, Bonini C, Magnani Z, et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci U S A. 2006;103:1457-1462.

31. Hacein-Bey-Abina S, von KC, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348:255-256.

32. Marshall E. Gene therapy. Second child in French trial is found to have leukemia. Science. 2003;299:320.

33. Check E. Gene therapy put on hold as third child develops cancer. Nature. 2005;433:561.

34. Yee C, Thompson JA, Roche P, et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo. J Exp Med. 2000;192:1637-1644.

35. Vierboom MP, Nijman HW, Offringa R, et al. Tumor eradication by wild-type p53-specific cytotoxic T lymphocytes. J Exp Med. 1997;186:695-704.

36. Spiotto MT, Fu YX, Schreiber H. Tumor immunity meets autoimmunity: antigen levels and dendritic cell maturation. Curr Opin Immunol. 2003;15:725-730.

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Introduction

Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

Adoptive T cell transfer for tumor immunotherapy

Adoptive transfer of allogeneic hematopoietic stem cells (HSC) is an established treatment for hematological malignancies. Donor T cells are responsible for mediating the graft-versus- leukemia effect, but this is associated with graft-versus-host disease in up to 50% of transplant recipients. One of the most exciting applications of TCR gene transfer is the ability to generate autologous T cells that recognize leukemia or tumor antigens (Figure 1). There are a number of tumor associated antigens (TAA) that are being evaluated as targets for the immunotherapy of malignancies. However, while they are over-expressed on tumors, they are also expressed on normal tissues, albeit at low levels. Autologous T cells which naturally recognize tumor antigens with high affinity are subject to tolerance mechanisms such as deletion or anergy. Hence, although autologous T cell responses against tumor antigens can be detected in patients with malignancies, they are generally of low avidity. Since it has been shown that the transduced T cell population demonstrates the same functional avidity as the original parent T cell from which the TCR genes are cloned, one of the advantages of TCR gene therapy is that a high avidity TCR can be selected for transfer into target T cells. There are several methods by which high avidity cytotoxic T lymphocytes (CTL) specific for TAAs can be generated. Immunization of HLA transgenic mice, the allo-restricted approach, in vitro mutagenesis of TCRs, and in vitro selection using phage display have been used to generate TCRs with increased peptide/MHC binding affinity.

Figure 1. TCR gene transfer.
(i) A T cell bearing the appropriate TCR is identified, (ii) the alpha and beta TCR chains genes are isolated and cloned into a retroviral vector, (iii) the vector is used to transfect a packaging cell line which produces viral particles containing the genes of interest: (iv). (v) Target T cells are transduced with the recombinant viral particles; (vi) when the genes integrate into the host DNA the target cells express the desired TCR.

2008-2-en-King-et-al-Figure-1.jpg


Transduced T cells have been shown to contribute to tumor clearance in murine models , and the first clinical trial of TCR gene transfer was recently reported. Retroviral gene transfer was used to transduce peripheral blood lymphocytes taken from patients with melanoma, with the genes encoding the α and β chains of a TCR with specificity for a MART 1 peptide presented by HLA-A*0201. The 17 patients in the gene transfer study were lymphodepleted prior to receiving autologous T cells transduced with the MART-1 TCR. The engineered T cells persisted in 15 patients, and the two patients with the highest levels of circulating anti-melanoma T cells showed objective regression of metastatic lesions and remained in remission 18 months after treatment. The results of this study prove that retroviral TCR gene transfer can be used to confer anti-tumor specificity upon a large number of autologous T cells, and that these T cells can engraft in patients and persist at high levels long term.

TCR gene transfer to generate anti viral T cells

A further application for TCR gene transfer is to generate virus-specific T cells for the treatment of immunosuppressed patients who have undergone HSC transplantation. After GvHD, post transplant viral infection is the next major cause of morbidity and mortality in transplant recipients. Adoptive T cell transfer has been shown to be an effective treatment for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection in transplant recipients. Donor-derived CMV specific CD8 T cells which had been expanded in vitro were then infused into HSC transplant recipients with good effect. Similarly, donor-derived EBV specific T cell lines have been used to treat EBV related post-transplant proliferative disease. However, the major limitation of this strategy is that it is not possible to generate virus-specific CTL from all HSC donors using in vitro expansion techniques. TCR gene transfer has the ability to overcome this obstacle and confer upon donor T cells TCR specificities that are not present in the endogenous donor repertoire. This technique also has the advantage of generating large numbers of virus-specific CTL far more rapidly than standard in vitro expansion approaches, which would be of clear benefit in a clinical scenario where a patient presents acutely with significant morbidity. While clinical trial data is still pending, this strategy has great potential for the treatment of viral infections in HSC recipients.

Augmenting TCR gene transfer

In recent years, several groups have explored the means by which TCR gene transfer can be optimized. Modern vector designs aim to increase exogenous TCR expression on target cells by combining α and β chains in a single vector linked by viral self cleaving 2A sequences, rather than internal ribosome entry sites. Codon optimization of TCR gene sequences has also been shown to result in increased TCR expression in human CD8+ T cells, and increased antigen-specific IFNγ release.

In parallel with these vector modifications, recent research efforts have been directed towards increasing the preferential pairing of exogenous α and β chains with each other. It has been demonstrated that exogenous TCRs are able to mispair with endogenous TCR chains (Figure 2). Any mispairing may reduce the expression density and hence the efficacy of the desired TCR, since the density of TCR expression on the cell surface has been shown to correlate with avidity. A number of strategies have recently been employed to address this issue. TCRs have been engineered to include an additional cysteine residue in the constant regions of the α and β chains, resulting in the formation of a second disulphide bond between them. T cells transduced with cysteine-modified receptors showed increased tetramer binding, secreted more cytokine, and showed increased antigen specific lysis when co-cultured with specific tumor cell lines, compared with T cells expressing wild type TCR. Hybrid TCRs have also been designed to incorporate murine constant regions and human variable regions. These hybrid TCRs show reduced mispairing with fully human TCRs when introduced into human T cells, combined with superior cell surface expression and biological activity. However, there is a possibility that a human host will mount an immune response against the murine component of such a TCR. In the same way that murine monoclonal antibodies have become increasingly humanized for clinical use, it is likely that murinization of the TCR constant region will be minimized to reduce its immunogenicity, if this strategy is to be used in a clinical setting.

2008-2-en-King-et-al-Figure-2.jpg

Figure 2: exogenous and endogenous TCR chains compete for CD3 molecules for surface expression, and can mispair to form mixed dimers of unknown specificity. TCR α and β chains must form a complex with the ζ,δ,ε and γ CD3 chains in order for the TCR to be expressed on the cell surface. Following retroviral TCR gene transfer, there is competition between the endogenous TCR (A) and the exogenous TCR (B) for CD3. Increasing the availability of CD3 chains could increase the density of expression, and hence functional avidity, of the exogenous TCR. C: mispairing of endogenous and exogenous TCR chains leads to mixed dimer formation. These TCR have the potential to be autoreactive, and also reduce the CD3 available for expression of the desired TCR (B).


Strategies such as murinization of constant domains and cysteine modification of TCR chains reduce mispairing and increase the "strength" of a TCR. Recent data has shown that "strong" TCRs are expressed at high levels following retroviral gene transfer, whereas "weak" TCRs are poorly expressed because they compete poorly against the endogenous TCR repertoire for CD3 molecules. Research is ongoing into whether there are specific amino acid sequences in the TCR constant domain that contribute towards "strength." An alternative strategy that is currently being investigated is the cotransduction of TCR along with the genes encoding the CD3 complex. Endogenous and exogenous TCR chains are in competition for a limited pool of CD3 molecules, and exogenous TCR chains are likely to be present in excess, since their production is under the control of a retroviral promoter. The expectation would be that cotransducing with both TCR and CD3 molecules would increase the availability of CD3 molecules, which would have a more profound effect on expression of the exogenous TCR whose α and β chains are present in excess. 

Safety concerns

Although there is no evidence of off-target toxicity in murine models to date, it has been demonstrated that exogenous TCR are able to mispair with endogenous TCR chains, resulting in the expression of TCRs that have not undergone thymic education. These TCR, with unpredictable specificities, have the potential to be autoreactive. The strategies described above have been employed to both reduce mispairing and to increase expression of the desired TCR. Research is ongoing into alternative means by which the risk of mispairing may be reduced. It has recently been shown that TCR α and β chains which have each been linked to a CD3ζ chain did not mispair with endogenous TCR chains in a Jurkat T cell model. Since γδ TCR chains cannot mispair with αβ TCR chains, transferring αβ TCR chains into γδ T cells should not result in any mispairing, and has previously been shown to result in the expression of exogenous αβ TCR which produce cytokine and lyse target cells in an antigen-specific manner. Transduction of viral-specific T cells is a strategy by which the potential number of mixed dimers can be reduced; since anti viral responses consist of T cells with a restricted TCR repertoire. An alternative approach would be to transduce HSC with TCR genes. In vitro generation of mature, antigen-specific T cells by TCR gene transfer into thymus or cord-derived HSC has recently been reported. Allelic exclusion of the endogenous TCR β chain meant that mixed dimer formation was reduced, but not entirely avoided due to some endogenous α chain expression. However, while the risk of transformation of mature T cells is low, the risk in HSC may be higher, making this a less appealing strategy. In a clinical trial of X linked severe combined immunodeficiency disease, 4 children treated with HSC retrovirally transduced with the common γ chain developed T lymphoproliferative disorders. This was later found to be secondary to retroviral insertion into the LMO-2 oncogene intron on chromosome 11, with subsequent upregulation. Although there is no evidence to date of transformation of mature T cells with retroviral vectors, the use of lentiviral vectors is also being investigated, since it has been shown that lentiviral vectors insert near promoters at a lower frequency.

While there is a concern that low avidity, TAA specific CTL from the autologous repertoire may not be efficacious, high avidity, self-reactive CTL may pose the opposite problem. The majority of targets for tumor immunotherapy are over-expressed self proteins, and therefore there is a risk that targeting TAA may result in autoimmune damage. In murine models and in clinical trials it has been demonstrated that the successful induction of CTL responses against melanoma TAAs (such as melan A or gp100) has been associated with the development of vitiligo. T cell therapies targeting TAAs with a more ubiquitous distribution have not been studied in the same detail as yet, although it has been shown that high avidity p53 specific CTLs (generated in p53-/- transgenic mice) can provide tumor protection without causing autoimmune damage in mice. A moderately high affinity TCR was used in the TCR gene therapy trial, and work is now ongoing by the same group to test a higher avidity TCR. It remains to be seen whether any morbidity resulting from autoimmune disease outweighs the associated anti tumor benefit. A balance needs to be struck between TAA specific CTL which are of high enough avidity to mediate tumor killing, but which do not cause significant autoimmune damage to healthy tissue. It is likely that a large discrepancy between the expression level of the target antigen on tumor tissue compared to that on normal tissue will be an important factor in this regard, as will the pattern of distribution of the TAA in normal tissue. 

Conclusion

Although TCR gene transfer holds promise, there may yet be obstacles to overcome with respect to either the safety or the efficacy of this strategy. While mispairing of endogenous and exogenous TCR chains may result in off target toxicity, high avidity CTL may cause on target toxicity by attacking normal tissues that express low levels of the target antigen. However, recent clinical trial data has demonstrated that TCR gene transfer is an effective means by which a defined population of antigen specific T cells can be generated which persist following adoptive transfer into patients. Research is ongoing to address the safety issues and to improve the expression of retrovirally introduced TCRs. Furthermore, while the adoptive transfer of antigen specific regulatory cells has been less well explored to date, this warrants further investigation as there are a number of potential clinical applications for such a strategy. Although unanswered questions remain, it is evident that TCR gene transfer holds clear promise for the treatment of malignancies and viral infections and may have potential to treat unwanted immunopathology in the future. 

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Department of Immunology, Royal Free Hospital, University College London, UK

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Department of Immunology, Royal Free Hospital, University College London, UK

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Introduction

Tregs play a crucial role in maintaining immune tolerance during normal homeostasis as well as controlling and resolving active immune responses [1]. Several different groups of regulatory T cells have been identified, which play varying roles in the maintenance of physiological immune tolerance [2]. The most intensely studied of these are the FoxP3+ Tregs, which will be the focus of the remainder of this review. Until recently it was thought that FoxP3+ Tregs were generated exclusively in the thymus, hence their common description as natural Tregs. However, it has now been demonstrated that a proportion of FoxP3+ Tregs are generated in the periphery from conventional CD4+ T cells, termed adaptive Tregs [3]. FoxP3+ Tregs exert regulation via a number of different mechanisms, which at present remain poorly defined. The known mediators of these mechanisms can broadly be split into the contact-dependent mechanisms, including membrane-bound TGFβ [4], CTLA-4 [5, 6] and intra-cellular/peri-cellular adenosine compound generation [7, 8]; and the contact-independent cytokine mediated mechanisms, which include the effects of IL-10 [9] and TGFβ [10].

TCR gene transfer into Tregs

Like conventional T cells, Tregs require stimulation via TCR interaction with a cognate peptide: MHC complex in order to exert suppression [11]; therefore they would be malleable to specificity re-direction by TCR gene transfer. Tregs are capable of potently suppressing T cell responses at naïve, effector and memory stages. In addition they have also been demonstrated to act on various other immune cells, including B cells [12], DCs [5], and monocytes [13]. Many aspects of Treg-mediated suppression make them ideal candidates for Ag targeted therapy of immuno-pathology. Firstly, although Tregs require Ag specific stimulation via the TCR, they suppress in an Ag non-specific manner [11]. This phenomenon, termed linked suppression, means that a Treg of one specificity can suppress a conventional T cell of an unrelated specificity provided the cognate Ag for both is expressed on the same antigen-presenting cell (APC). Utilizing this phenomenon of linked suppression along with an intelligent Ag targeting, it would be possible to direct suppression toward the organ or tissue which is affected regardless of whether the causative epitope, or indeed any of the epitopes additionally involved by antigenic spreading, have been identified. Secondly, Treg-mediated tolerance against one peptide specificity can be transferred to other related specificities [14]. This process, referred to as infectious tolerance, is mediated by modulation of dendritic cells (DC) and de novo induction of adaptive Tregs, and would allow for the generation of long lasting multi-epitope mediated tolerance regardless of the limits of the Ag specificity and persistence of the transferred Tregs. Thirdly, Tregs are an endogenous immune control mechanism, present in all healthy individuals. It is clear that all normal inflammatory protective immune responses are elicited in the presence of Tregs, indicating that re-establishing tolerance via Treg adoptive transfer would not preclude future protective immune responses. This is supported by skin graft models, in which Treg-induced tolerance to allo-grafted skin on the flank was not affected by the rejection of a distinct skin allograft on the contra-lateral flank [15]. If these properties of Tregs could be effectively harnessed they could provide the therapeutic panacea for clinical immune pathology, namely a long lasting Ag-specific control without the complications of a general immune suppression.

2008-2-en-Wright-et-al-Figure-1_01.jpg

Figure 1. Linked suppression and infectious tolerance. Two important concepts of Treg function are linked suppression and infectious tolerance. Linked suppression allows that a Treg of specificity A can suppress a conventional T cell of specificity B provided the cognate antigen for both is expressed on the same antigen presenting cell. This suppression can occur either via the intermediary of the antigen-presenting cell or directly by soluble mediators or Treg to T cell interaction. Infectious tolerance is the process whereby the tolerogenic state of the Treg is transferred to a previously non-tolerogenic T cell. Again, this phenomenon can occur indirectly, via the generation of a tolerogenic DC or directly via interactions between the Treg and conventional T cell.

Tregs in autoimmunity

There are numerous examples of the use of Tregs to prevent murine models of autoimmunity. However, to the best of our knowledge there are only three examples of reversion of ongoing autoimmunity using Tregs. Intriguingly, two of those studies were carried out using Ag specific Tregs [16, 17]. The third was carried out in a model where the Treg niche was empty before adoptive transfer of the Tregs [18]. It is postulated that the reconstitution of this niche may have created a situation whereby Ag-specific expansion of the Tregs was favored – hence providing the level of Ag specificity required to reverse the ongoing disease. It is compelling that in the former study non-obese diabetic mice were reverted from ongoing autoimmunity using a Treg population specific for a single pancreatic Ag [17]. In this elegant study the authors demonstrated that a transgenic monoclonal Treg population was capable of reverting disease by controlling a multiple epitope T cell responses against peptides derived from an entire organ. This work is a clear indication that Ag specificity is required to revert ongoing autoimmunity, and that Tregs specific to a single disease-related Ag may be sufficient to control a complex and advanced immune response. The importance of Ag specificity in autoimmunity, therefore, is of clear importance: autoimmunity is rarely a predictable disease and typically presents after the establishment of a strong immune response and considerable damage.

Tregs in transplantation

Hematopoietic stem cell transplantation is an effective treatment for a number of hematological diseases, but is accompanied by the potential for development of graft versus host disease (GvHD). Several murine studies have demonstrated the efficacy of adoptive Treg transfer in curing GvHD. In addition to this, whilst the adoptive transfer of Tregs in murine models could prevent GvHD, they did not impact on the advantageous graft versus leukemia (GvL) response. The need for Ag-specific targeting in the prevention of GvHD is less clear than is seen in an autoimmune setting. This is probably due to two factors. Firstly, the Tregs are being adoptively transferred into irradiated and hence lymphopenic hosts, and the subsequent expansion of the Tregs to fill their niche may allow for the preferential expansion of allo-Ag specific Tregs. Secondly, and directly related to the first point, there is likely to be a larger proportion of allo-Ag specific Tregs than auto-Ag specific Tregs in the autoimmune situation. Interestingly in GvHD, Ag-specific Tregs offer only marginal improvement in protection upon adoptive transfer when compared with polyclonal Tregs [19, 20]. These promising pre-clinical studies using polyclonal Tregs have encouraged two separate groups to begin early clinical trials in adoptive Treg transfer in the treatment of human GvHD. However, the potential efficacy of polyclonal Tregs in the treatment of GvHD does not negate the need to examine the potential of Ag-targeted Tregs to treat this disease. Indeed, it should be noted that in all three of the murine studies quoted here, very high number of Tregs were transferred to induce tolerance (around 1:1 Treg:conventional T cell). It is likely that if these Tregs were Ag-specific the number could be reduced substantially. In addition, work is ongoing to identify the distinguishing factors between the development of GvHD and GvL; any advancement in our understanding of this difference will likely allow for targeted Treg therapy to prevent GvHD without impacting on GvL.

There is a clear correlation in the clinical setting between solid organ transplant tolerance and Treg levels. In contrast to autoimmune and GvHD settings, prevention of solid organ rejection by polyclonal Treg transfer in murine models has not been demonstrated. However, numerous studies have demonstrated that the transfer of Tregs from previously tolerized mice is sufficient to prevent rejection of solid organs [21]. More recently, it has been additionally demonstrated that Tregs expanded in vitro against allo-antigen are capable of mediating prevention of rejection [15, 22]. These latter studies also highlighted the importance of Tregs directed against indirect allo-Ag in preventing chronic rejection. Both strategies demonstrate the need for Ag specificity targeted against the most appropriate Ag to induce Treg-mediated tolerance.

FoxP3+ Tregs: Potential for antigen specific therapy

It is clear that Ag specificity will be an important factor in successfully translating the promising pre-clinical data into a clinical setting. There are many obstacles to generating Ag-specific Tregs, mainly related to the physiological nature of Tregs as a small population of poorly responsive (in vitro) T cells. Whilst in vitro protocols to expand Ag specific Tregs have advanced in recent years [23] they still represent at present a labor intensive, expensive, and flawed process. Identification of a functional Treg population is at present an imperfect process. Whilst the transcription FoxP3 is generally considered as the only reliable Treg marker, as an intracellular protein it is of no use in identifying functional Tregs. For this reason Tregs are generally identified by a constellation of surface markers, mainly CD4 and CD25. However, CD4+CD25+ population also includes a contaminating fraction of activated conventional T cells. Expansion of this bulk population—whether Ag-specific or polyclonal—leads to an outgrowth of this contaminating conventional T cells population [24]. The more expansion required, the more outgrowth of these cells is seen. The numerous rounds of stimulation required to achieve a sufficient numbers of Ag-specific Tregs for effective treatment in a human setting, if at all possible, would undoubtedly lead to substantial outgrowth of this contaminating population. This contamination population of conventional T cells could potentially be a risk in exacerbating disease. Numerous surface markers have been added to CD4+CD25+ in identifying Tregs (GITR, CD127, CD39, FR4, HLA-DR CD45RA) [25-29] and although many of them allow for higher purity Treg sorting, each additional parameter leads to a decrease in the proportion of Tregs obtained. This is a practical problem when dealing with a population of cells already limited by their paucity.

We are currently examining TCR gene transfer into bead-sorted CD4+CD25+ Tregs. We have been consistently able to express a TCR of known specificity in 60-90% of polyclonally activated Tregs after a single round of activation and transduction. These Tregs demonstrate in vitro Ag-dependent linked suppression of a naïve TCR transgenic CD8+ T cells up-to 30 fold greater than that seen in absence of Ag. With appropriate modifications, including exploration of alternative Treg sorting strategies and optimizing (i.e., reducing) proliferation and transduction protocols, this approach could be used to generate large populations of Ag-specific highly pure Tregs. Other advantages of this approach include the ability to select TCR from outside the normal Treg TCR repertoire. It may be possible to use higher affinity TCR generated in the conventional T cell repertoire or indeed generate high affinity TCR using the allo-restricted strategy [30]. However, it is also important to acknowledge that safety issues must be addressed before the routine use of TCR gene transfer into Tregs. Briefly, those risks primarily involve the danger of development of malignancy caused by insertional mutagenesis and the potential for the creation of unknown specificity TCR from mis-pairing of the endogenous and introduced TCR. The risk of insertional mutagenesis is greatly decreased in mature T cells compared to hematopoietic stem cells, but it remains an important consideration before proceeding with any form of stable gene insertion. The second issue is the generation of novel specificity TCR through mis-pairing of the introduced TCR alpha or beta chains with the corresponding alpha and beta chains endogenously expressed in each T cell. These novel TCR have not been thymically educated and may potentially be strongly self-reactive. It is unclear what the effect of any self-reactive TCR generated through mis-pairing might have in Tregs. It is possible that TCR mis-pairing may be less of an issue in Tregs which are proposed to have a bias in TCR selection towards self specific Ag:MHC complexes. However, it cannot be ruled out that Tregs with a TCR affinity greater than that normally selected during Treg TCR selection may mediate inappropriate suppression. There is considerable effort being employed in addressing these issues in conventional T cells and any advance in TCR gene therapy in that setting will almost certainly be applicable Tregs (see King et al. in this issue for more in-depth review of these issues).

Genetically induced Treg-like T cells

As well as the use of naturally occurring Tregs to treat immune-pathology, there have also been a number of studies using genetically modified “Treg-like” cells. It is well documented that ectopic expression of the regulatory transcription factor FoxP3 induces Treg-like function in conventional murine T cells [31]. Similar to the study described earlier in NOD mice, two studies demonstrated the transduction of FoxP3 into pancreatic islet specific transgenic CD4+ and CD8+ T cells was capable of ameliorating diabetes in NOD mice [32, 33]. FoxP3 expression in polyclonal T cells had no affect in these models. Similar findings have been demonstrated in GvHD settings [34] and solid organ transplantation [35]. Transfer of this concept into a human setting is hindered by subtle differences in the expression and function of FoxP3 in human T cells. Human conventional T cells have been shown to transiently up-regulate FoxP3 subsequent to activation, without the acquisition of any regulatory function. In addition, the ectopic expression of FoxP3 does not consistently instill the same level of regulatory function in human T cells [36]. However, a recent study has demonstrated that lenti-viral mediated expression of FoxP3 in human T cells under a constitutive (i.e., activation state independent) promoter produces consistently efficient regulatory like phenotype [37].

We are currently examining the potential of co-transfer of TCR genes along with the FoxP3 transcription factor using a single tri-cistronic vector to generate functionally suppressive T cells. Subsequent to transduction these cells show limited proliferation and little or no IFNγ and IL-2 secretion. Whilst in our hands the level of Ag-dependent suppression elicited by these T cells is less marked than TCR expressing CD4+CD25+ Tregs, it has proven a reliable method of generating large numbers of homogenous TCR expressing Treg-like T cells. It should also be noted that although the in vitro linked suppression assay is a useful indicator of suppressive ability it is not always completely predictive of the level of suppression in vivo. It will be interesting to compare these two types of regulatory T cells in vivo.

2008-2-en-Wright-et-al-Figure-2_01.jpg

Figure 2. Generating antigen specific Tregs using TCR gene transfer; two approaches. Using lenti or retro viral gene transfer it is possible to generate antigen-specific suppressive T cells. Two strategies have been utilized to achieve this: (A) Gene transfer of TCR alpha and beta chains of a TCR of known specificity into a poly-clonally activated population of sorted Tregs, and (B) Co-transfer of the genes encoding TCR alpha/beta chains and the regulatory transcription factor FoxP3 into a poly-clonally activated population of conventional CD4+ T cells.

Conclusion

There is now a substantial body of evidence in pre-clinical models for the efficacy of Tregs in the treatment of immuno-pathology. However, as yet there are only two ongoing human clinical trials, both in a GvHD setting. Many unanswered questions and obstacles stand in the way of utilizing Tregs to their maximal effect. Not least amongst these is the question of how to generate sufficiently large populations of Ag-specific regulatory T cells. Here we have highlighted the importance of Ag specificity and proposed that TCR gene transfer into polyclonally expanded Tregs as well as artificially generating FoxP3+ TCR expressing T cells may provide an efficient way of generating large populations of Ag specific Tregs. Studies are ongoing as to the efficacy of each of these approaches in models of auto-immunity and GvHD, and from initial indications we expect these methods to show considerable efficacy in the treatment of immune mediated pathology.

Acknowledgements

The authors would like to thank Mario Perro for his constructive discussions.

References

1. Sakaguchi S, Yamaguchi T, Nomura T, and Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775-787.

2. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25:195-201.

3. Coombes JL, Siddiqui KR, rancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, and Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757-1764.

4. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, and Strober W. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172:834-842.

5. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, and Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4:1206-1212.

6. Read S, Malmstrom V, and Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295-302.

7. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, and Robson SC. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257-1265.

8. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, and Schmitt E. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med. 2007;204:1303-1310.

9. Asseman C, Read S, and Powrie F. Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J Immunol. 2003;171:971-978.

10. Powrie F, Carlino J, Leach MW, Mauze S, and Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669-2674.

11. Thornton AM and Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164:183-190.

12. Lim HW, Hillsamer P, Banham AH, and Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175:4180-4183.

13. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, and Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl Acad Sci U S A. 2007;104:19446-19451.

14. Waldmann H, Adams E, Fairchild P, and Cobbold S. Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol Rev. 2006;212:301-313.

15. Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, and Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood. 2007;109:827-835.

16. Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A, Yang H, Suthanthiran M, Mojsov S, and Steinman RM. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204:191-201.

17. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, and Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199:1455-1465.

18. Mottet C, Uhlig HH, and Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003;170:3939-3943.

19. Yamazaki S, Patel M, Harper A, Bonito A, Fukuyama H, Pack M, Tarbell KV, Talmor M, Ravetch JV, Inaba K, and Steinman RM. Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci U S A. 2006;103:2758-2763.

20. Trenado A, Sudres M, Tang Q, Maury S, Charlotte F, Gregoire S, Bonyhadi M, Klatzmann D, Salomon BL, and Cohen JL. Ex vivo-expanded CD4+CD25+ immunoregulatory T cells prevent graft-versus-host-disease by inhibiting activation/differentiation of pathogenic T cells. J Immunol. 2006;176:1266-1273.

21. Wood KJ and Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol. 2003;3:199-210.

22. Joffre O, Santolaria T, Calise D, Al ST, Hudrisier D, Romagnoli P, and van Meerwijk JP. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med. 2008;14:88-92.

23. Allan SE, Broady R, Gregori S, Himmel ME, Locke N, Roncarolo MG, Bacchetta R, and Levings MK. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev. 2008;223:391-421.

24. Tang Q and Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006;212:217-237.

25. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, and Sakaguchi S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3:135-142.

26. Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, and Fazekas de St GB. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693-1700.

27. Yamaguchi T, Hirota K, Nagahama K, Ohkawa K, Takahashi T, Nomura T, and Sakaguchi S. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity. 2007;27:145-159.

28. Baecher-Allan C, Wolf E, and Hafler DA. MHC class II expression identifies functionally distinct human regulatory T cells. J Immunol. 2006;176:4622-4631.

29. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, and Edinger M. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. 2006;108:4260-4267.

30. Sadovnikova E and Stauss HJ. Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc Natl Acad Sci U S A. 1996;93:13114-13118.

31. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, and Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22:329-341.

32. Jaeckel E, von BH, and Manns MP. Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes. 2005;54:306-310.

33. Peng J, Dicker B, Du W, Tang F, Nguyen P, Geiger T, Wong FS, and Wen L. Converting antigen-specific diabetogenic CD4 and CD8 T cells to TGF-beta producing non-pathogenic regulatory cells following FoxP3 transduction. J Autoimmun. 2007;28:188-200.

34. Albert MH, Liu Y, Anasetti C, and Yu XZ. Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation. Eur J Immunol. 2005;35:2598-2607.

35. Chai JG, Xue SA, Coe D, Addey C, Bartok I, Scott D, Simpson E, Stauss HJ, Hori S, Sakaguchi S, and Dyson J. Regulatory T cells, derived from naive CD4+. Transplantation. 2005;79:1310-1316.

36. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, Stray-Pedersen A, Ocheltree EL, Greenberg PD, Ochs HD, and Rudensky AY. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci U S A. 2006;103:6659-6664.

37. Allan SE, Alstad AN, Merindol N, Crellin NK, Amendola M, Bacchetta R, Naldini L, Roncarolo MG, Soudeyns H, and Levings MK. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther. 2008;16:194-202.

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Introduction

Tregs play a crucial role in maintaining immune tolerance during normal homeostasis as well as controlling and resolving active immune responses [1]. Several different groups of regulatory T cells have been identified, which play varying roles in the maintenance of physiological immune tolerance [2]. The most intensely studied of these are the FoxP3+ Tregs, which will be the focus of the remainder of this review. Until recently it was thought that FoxP3+ Tregs were generated exclusively in the thymus, hence their common description as natural Tregs. However, it has now been demonstrated that a proportion of FoxP3+ Tregs are generated in the periphery from conventional CD4+ T cells, termed adaptive Tregs [3]. FoxP3+ Tregs exert regulation via a number of different mechanisms, which at present remain poorly defined. The known mediators of these mechanisms can broadly be split into the contact-dependent mechanisms, including membrane-bound TGFβ [4], CTLA-4 [5, 6] and intra-cellular/peri-cellular adenosine compound generation [7, 8]; and the contact-independent cytokine mediated mechanisms, which include the effects of IL-10 [9] and TGFβ [10].

TCR gene transfer into Tregs

Like conventional T cells, Tregs require stimulation via TCR interaction with a cognate peptide: MHC complex in order to exert suppression [11]; therefore they would be malleable to specificity re-direction by TCR gene transfer. Tregs are capable of potently suppressing T cell responses at naïve, effector and memory stages. In addition they have also been demonstrated to act on various other immune cells, including B cells [12], DCs [5], and monocytes [13]. Many aspects of Treg-mediated suppression make them ideal candidates for Ag targeted therapy of immuno-pathology. Firstly, although Tregs require Ag specific stimulation via the TCR, they suppress in an Ag non-specific manner [11]. This phenomenon, termed linked suppression, means that a Treg of one specificity can suppress a conventional T cell of an unrelated specificity provided the cognate Ag for both is expressed on the same antigen-presenting cell (APC). Utilizing this phenomenon of linked suppression along with an intelligent Ag targeting, it would be possible to direct suppression toward the organ or tissue which is affected regardless of whether the causative epitope, or indeed any of the epitopes additionally involved by antigenic spreading, have been identified. Secondly, Treg-mediated tolerance against one peptide specificity can be transferred to other related specificities [14]. This process, referred to as infectious tolerance, is mediated by modulation of dendritic cells (DC) and de novo induction of adaptive Tregs, and would allow for the generation of long lasting multi-epitope mediated tolerance regardless of the limits of the Ag specificity and persistence of the transferred Tregs. Thirdly, Tregs are an endogenous immune control mechanism, present in all healthy individuals. It is clear that all normal inflammatory protective immune responses are elicited in the presence of Tregs, indicating that re-establishing tolerance via Treg adoptive transfer would not preclude future protective immune responses. This is supported by skin graft models, in which Treg-induced tolerance to allo-grafted skin on the flank was not affected by the rejection of a distinct skin allograft on the contra-lateral flank [15]. If these properties of Tregs could be effectively harnessed they could provide the therapeutic panacea for clinical immune pathology, namely a long lasting Ag-specific control without the complications of a general immune suppression.

2008-2-en-Wright-et-al-Figure-1_01.jpg

Figure 1. Linked suppression and infectious tolerance. Two important concepts of Treg function are linked suppression and infectious tolerance. Linked suppression allows that a Treg of specificity A can suppress a conventional T cell of specificity B provided the cognate antigen for both is expressed on the same antigen presenting cell. This suppression can occur either via the intermediary of the antigen-presenting cell or directly by soluble mediators or Treg to T cell interaction. Infectious tolerance is the process whereby the tolerogenic state of the Treg is transferred to a previously non-tolerogenic T cell. Again, this phenomenon can occur indirectly, via the generation of a tolerogenic DC or directly via interactions between the Treg and conventional T cell.

Tregs in autoimmunity

There are numerous examples of the use of Tregs to prevent murine models of autoimmunity. However, to the best of our knowledge there are only three examples of reversion of ongoing autoimmunity using Tregs. Intriguingly, two of those studies were carried out using Ag specific Tregs [16, 17]. The third was carried out in a model where the Treg niche was empty before adoptive transfer of the Tregs [18]. It is postulated that the reconstitution of this niche may have created a situation whereby Ag-specific expansion of the Tregs was favored – hence providing the level of Ag specificity required to reverse the ongoing disease. It is compelling that in the former study non-obese diabetic mice were reverted from ongoing autoimmunity using a Treg population specific for a single pancreatic Ag [17]. In this elegant study the authors demonstrated that a transgenic monoclonal Treg population was capable of reverting disease by controlling a multiple epitope T cell responses against peptides derived from an entire organ. This work is a clear indication that Ag specificity is required to revert ongoing autoimmunity, and that Tregs specific to a single disease-related Ag may be sufficient to control a complex and advanced immune response. The importance of Ag specificity in autoimmunity, therefore, is of clear importance: autoimmunity is rarely a predictable disease and typically presents after the establishment of a strong immune response and considerable damage.

Tregs in transplantation

Hematopoietic stem cell transplantation is an effective treatment for a number of hematological diseases, but is accompanied by the potential for development of graft versus host disease (GvHD). Several murine studies have demonstrated the efficacy of adoptive Treg transfer in curing GvHD. In addition to this, whilst the adoptive transfer of Tregs in murine models could prevent GvHD, they did not impact on the advantageous graft versus leukemia (GvL) response. The need for Ag-specific targeting in the prevention of GvHD is less clear than is seen in an autoimmune setting. This is probably due to two factors. Firstly, the Tregs are being adoptively transferred into irradiated and hence lymphopenic hosts, and the subsequent expansion of the Tregs to fill their niche may allow for the preferential expansion of allo-Ag specific Tregs. Secondly, and directly related to the first point, there is likely to be a larger proportion of allo-Ag specific Tregs than auto-Ag specific Tregs in the autoimmune situation. Interestingly in GvHD, Ag-specific Tregs offer only marginal improvement in protection upon adoptive transfer when compared with polyclonal Tregs [19, 20]. These promising pre-clinical studies using polyclonal Tregs have encouraged two separate groups to begin early clinical trials in adoptive Treg transfer in the treatment of human GvHD. However, the potential efficacy of polyclonal Tregs in the treatment of GvHD does not negate the need to examine the potential of Ag-targeted Tregs to treat this disease. Indeed, it should be noted that in all three of the murine studies quoted here, very high number of Tregs were transferred to induce tolerance (around 1:1 Treg:conventional T cell). It is likely that if these Tregs were Ag-specific the number could be reduced substantially. In addition, work is ongoing to identify the distinguishing factors between the development of GvHD and GvL; any advancement in our understanding of this difference will likely allow for targeted Treg therapy to prevent GvHD without impacting on GvL.

There is a clear correlation in the clinical setting between solid organ transplant tolerance and Treg levels. In contrast to autoimmune and GvHD settings, prevention of solid organ rejection by polyclonal Treg transfer in murine models has not been demonstrated. However, numerous studies have demonstrated that the transfer of Tregs from previously tolerized mice is sufficient to prevent rejection of solid organs [21]. More recently, it has been additionally demonstrated that Tregs expanded in vitro against allo-antigen are capable of mediating prevention of rejection [15, 22]. These latter studies also highlighted the importance of Tregs directed against indirect allo-Ag in preventing chronic rejection. Both strategies demonstrate the need for Ag specificity targeted against the most appropriate Ag to induce Treg-mediated tolerance.

FoxP3+ Tregs: Potential for antigen specific therapy

It is clear that Ag specificity will be an important factor in successfully translating the promising pre-clinical data into a clinical setting. There are many obstacles to generating Ag-specific Tregs, mainly related to the physiological nature of Tregs as a small population of poorly responsive (in vitro) T cells. Whilst in vitro protocols to expand Ag specific Tregs have advanced in recent years [23] they still represent at present a labor intensive, expensive, and flawed process. Identification of a functional Treg population is at present an imperfect process. Whilst the transcription FoxP3 is generally considered as the only reliable Treg marker, as an intracellular protein it is of no use in identifying functional Tregs. For this reason Tregs are generally identified by a constellation of surface markers, mainly CD4 and CD25. However, CD4+CD25+ population also includes a contaminating fraction of activated conventional T cells. Expansion of this bulk population—whether Ag-specific or polyclonal—leads to an outgrowth of this contaminating conventional T cells population [24]. The more expansion required, the more outgrowth of these cells is seen. The numerous rounds of stimulation required to achieve a sufficient numbers of Ag-specific Tregs for effective treatment in a human setting, if at all possible, would undoubtedly lead to substantial outgrowth of this contaminating population. This contamination population of conventional T cells could potentially be a risk in exacerbating disease. Numerous surface markers have been added to CD4+CD25+ in identifying Tregs (GITR, CD127, CD39, FR4, HLA-DR CD45RA) [25-29] and although many of them allow for higher purity Treg sorting, each additional parameter leads to a decrease in the proportion of Tregs obtained. This is a practical problem when dealing with a population of cells already limited by their paucity.

We are currently examining TCR gene transfer into bead-sorted CD4+CD25+ Tregs. We have been consistently able to express a TCR of known specificity in 60-90% of polyclonally activated Tregs after a single round of activation and transduction. These Tregs demonstrate in vitro Ag-dependent linked suppression of a naïve TCR transgenic CD8+ T cells up-to 30 fold greater than that seen in absence of Ag. With appropriate modifications, including exploration of alternative Treg sorting strategies and optimizing (i.e., reducing) proliferation and transduction protocols, this approach could be used to generate large populations of Ag-specific highly pure Tregs. Other advantages of this approach include the ability to select TCR from outside the normal Treg TCR repertoire. It may be possible to use higher affinity TCR generated in the conventional T cell repertoire or indeed generate high affinity TCR using the allo-restricted strategy [30]. However, it is also important to acknowledge that safety issues must be addressed before the routine use of TCR gene transfer into Tregs. Briefly, those risks primarily involve the danger of development of malignancy caused by insertional mutagenesis and the potential for the creation of unknown specificity TCR from mis-pairing of the endogenous and introduced TCR. The risk of insertional mutagenesis is greatly decreased in mature T cells compared to hematopoietic stem cells, but it remains an important consideration before proceeding with any form of stable gene insertion. The second issue is the generation of novel specificity TCR through mis-pairing of the introduced TCR alpha or beta chains with the corresponding alpha and beta chains endogenously expressed in each T cell. These novel TCR have not been thymically educated and may potentially be strongly self-reactive. It is unclear what the effect of any self-reactive TCR generated through mis-pairing might have in Tregs. It is possible that TCR mis-pairing may be less of an issue in Tregs which are proposed to have a bias in TCR selection towards self specific Ag:MHC complexes. However, it cannot be ruled out that Tregs with a TCR affinity greater than that normally selected during Treg TCR selection may mediate inappropriate suppression. There is considerable effort being employed in addressing these issues in conventional T cells and any advance in TCR gene therapy in that setting will almost certainly be applicable Tregs (see King et al. in this issue for more in-depth review of these issues).

Genetically induced Treg-like T cells

As well as the use of naturally occurring Tregs to treat immune-pathology, there have also been a number of studies using genetically modified “Treg-like” cells. It is well documented that ectopic expression of the regulatory transcription factor FoxP3 induces Treg-like function in conventional murine T cells [31]. Similar to the study described earlier in NOD mice, two studies demonstrated the transduction of FoxP3 into pancreatic islet specific transgenic CD4+ and CD8+ T cells was capable of ameliorating diabetes in NOD mice [32, 33]. FoxP3 expression in polyclonal T cells had no affect in these models. Similar findings have been demonstrated in GvHD settings [34] and solid organ transplantation [35]. Transfer of this concept into a human setting is hindered by subtle differences in the expression and function of FoxP3 in human T cells. Human conventional T cells have been shown to transiently up-regulate FoxP3 subsequent to activation, without the acquisition of any regulatory function. In addition, the ectopic expression of FoxP3 does not consistently instill the same level of regulatory function in human T cells [36]. However, a recent study has demonstrated that lenti-viral mediated expression of FoxP3 in human T cells under a constitutive (i.e., activation state independent) promoter produces consistently efficient regulatory like phenotype [37].

We are currently examining the potential of co-transfer of TCR genes along with the FoxP3 transcription factor using a single tri-cistronic vector to generate functionally suppressive T cells. Subsequent to transduction these cells show limited proliferation and little or no IFNγ and IL-2 secretion. Whilst in our hands the level of Ag-dependent suppression elicited by these T cells is less marked than TCR expressing CD4+CD25+ Tregs, it has proven a reliable method of generating large numbers of homogenous TCR expressing Treg-like T cells. It should also be noted that although the in vitro linked suppression assay is a useful indicator of suppressive ability it is not always completely predictive of the level of suppression in vivo. It will be interesting to compare these two types of regulatory T cells in vivo.

2008-2-en-Wright-et-al-Figure-2_01.jpg

Figure 2. Generating antigen specific Tregs using TCR gene transfer; two approaches. Using lenti or retro viral gene transfer it is possible to generate antigen-specific suppressive T cells. Two strategies have been utilized to achieve this: (A) Gene transfer of TCR alpha and beta chains of a TCR of known specificity into a poly-clonally activated population of sorted Tregs, and (B) Co-transfer of the genes encoding TCR alpha/beta chains and the regulatory transcription factor FoxP3 into a poly-clonally activated population of conventional CD4+ T cells.

Conclusion

There is now a substantial body of evidence in pre-clinical models for the efficacy of Tregs in the treatment of immuno-pathology. However, as yet there are only two ongoing human clinical trials, both in a GvHD setting. Many unanswered questions and obstacles stand in the way of utilizing Tregs to their maximal effect. Not least amongst these is the question of how to generate sufficiently large populations of Ag-specific regulatory T cells. Here we have highlighted the importance of Ag specificity and proposed that TCR gene transfer into polyclonally expanded Tregs as well as artificially generating FoxP3+ TCR expressing T cells may provide an efficient way of generating large populations of Ag specific Tregs. Studies are ongoing as to the efficacy of each of these approaches in models of auto-immunity and GvHD, and from initial indications we expect these methods to show considerable efficacy in the treatment of immune mediated pathology.

Acknowledgements

The authors would like to thank Mario Perro for his constructive discussions.

References

1. Sakaguchi S, Yamaguchi T, Nomura T, and Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775-787.

2. Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity. 2006;25:195-201.

3. Coombes JL, Siddiqui KR, rancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, and Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757-1764.

4. Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, and Strober W. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172:834-842.

5. Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, Belladonna ML, Fioretti MC, Alegre ML, and Puccetti P. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003;4:1206-1212.

6. Read S, Malmstrom V, and Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295-302.

7. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, Kuchroo VK, Strom TB, and Robson SC. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257-1265.

8. Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, Stoll S, Schild H, Staege MS, Stassen M, Jonuleit H, and Schmitt E. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med. 2007;204:1303-1310.

9. Asseman C, Read S, and Powrie F. Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J Immunol. 2003;171:971-978.

10. Powrie F, Carlino J, Leach MW, Mauze S, and Coffman RL. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med. 1996;183:2669-2674.

11. Thornton AM and Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164:183-190.

12. Lim HW, Hillsamer P, Banham AH, and Kim CH. Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol. 2005;175:4180-4183.

13. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, and Taams LS. CD4+CD25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc. Natl Acad Sci U S A. 2007;104:19446-19451.

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16. Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A, Yang H, Suthanthiran M, Mojsov S, and Steinman RM. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204:191-201.

17. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, and Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199:1455-1465.

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Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. 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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Department of Immunology, Royal Free Hospital, University College London, UK

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Department of Immunology, Royal Free Hospital, University College London, UK

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3408) "

Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
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Introduction

One of the main challenges of current leukemia research is the rarity of leukemias. The incidence of the various leukemias per 100,000 population/year range between around 1 (ALL) and 3-4 (CLL). The challenge is met by collaboration within cooperative groups and networks. Integration of leukemia research in Europe has been achieved to a high degree by cooperation at the level of national leukemia study groups, notably CML study groups, and by networking on national and European levels. The German CML Study Group (founded in 1982) was one of the cofounders of the European Investigators on CML Group (EI-CML), which was initiated by S. Tura, Bologna, in 1992. Fig. 1 shows the distribution of national CML study groups in Europe. On a German level, the German CML Study Group, together with other German leukemia study groups, started the German Competence Network “Akute und chronische Leukämien” (KNL) in 1997, which was funded by the German Ministry for Education and Research in 1999. The KNL, which combines all leukemia study groups in one country and the EI-CML, which combines all European groups cooperating on one leukemia, started the European LeukemiaNet (ELN) in 2002. This has been funded by the European Commission (EC) as a Network of Excellence (NoE) from 2004 onwards. Fig. 2 shows a flow diagram of the integration of leukemia research in Europe.

2008-2-en-Hehlmann-et-al-Fig-01.jpg

2008-2-en-Hehlmann-et-al-Fig-02.jpg


The groups forming the ELN all have convincing records in promoting leukemia research and improving survival for patients with leukemia. An example is the German CML Study Group, with its 600 participants in about 300 centers (Fig. 3). The group has conducted 5 major randomized studies over the past 25 years, which has improved survival of CML patients in Germany significantly from a median survival time of 3-4 years in 1983 to an expected median of about 25 years in 2008. Fig. 4 shows the improvement of survival in the trials of the German CML Study Group up to the present time. The current 5-year-survival of 93% in CML Study IV is better than that reported by any other study group.

2008-2-en-Hehlmann-et-al-Fig-3.jpg

2008-2-en-Hehlmann-et-al-Fig-4.jpg


The ELN, representing a collaboration of European leukemia study groups and their interdisciplinary partner groups, currently comprises 147 centers in 28 countries (Fig. 5), and involves about 1,000 physicians and scientists. The participating leukemia study groups are caring for some 10,000 leukemia patients across Europe. Cooperation is amongst 95 national leukemia study groups and 102 interdisciplinary partner groups as depicted in Figs. 6 and 7.

2008-2-en-Hehlmann-et-al-Fig-5.jpg

2008-2-en-Hehlmann-et-al-Fig-6_01.jpg

2008-2-en-Hehlmann-et-al-Fig-7.jpg


The goals of the ELN are to strengthen scientific and technological excellence in research and treatment of leukemias, promote clinical trials, prepare guidelines, and spread excellence. The success of the European approach in improving research and patient outcome is well illustrated by the paradigm chronic myeloid leukemia (CML).

Paradigm CML
1847: Term “Leukämie” coined
1960: Philadelphia chromosome discovered
1985: Fusion gene BCR-ABL detected
1990: BCR-ABL induces leukemia in mice
1998: BCR-ABL TK inhibitor imatinib in phase I
2008: Median survival (expected) 25 years

The term “leukemia” was coined  in 1847 [1]  to describe patients with what was later recognized to be CML. The name was later given to the whole group of leukemias. CML became the first neoplastic disease regularly associated with a chromosomal aberration, the Philadelphia-translocation (1960) [2]. CML also became the first neoplastic disease in which the molecular pathogenesis was elucidated. In 1985, the fusion gene BCR-ABL coding for a BCR-ABL fusion tyrosine kinase (TK) was detected [3], and in 1990 it was shown that BCR-ABL can induce leukemia in mice [4, 5]. This finding prompted experiments to inhibit BCR-ABL TK via specific inhibitors [6]. In 1998, a phase I trial with the TK inhibitor imatinib was started. The outcome was striking. Even patients with advanced disease achieved cytogenetic remissions [7]. This success was achieved by the cooperation of academic research with drug development by the pharmaceutical industry. The development of a “targeted” therapy for CML would not have been possible without close cooperation among all players in the field (trial groups, groups in cytogenetic and molecular research, pharmaceutical industry, etc.)

The molecular elucidation of CML pathogenesis relied heavily on earlier research with retroviruses and oncogenes. In this research an acute leukemia-inducing murine retrovirus, termed Abelson Virus, was found to contain a 5.6 kb long cellular RNA-sequence which, due to its oncogenic potential, was termed an “ABL oncogene”. In the human genome, ABL is located on chromosome 9, from where part of it is translocated to chromosome 22 in exchange for a larger piece of chromosome 22 called the “breakpoint cluster region” (BCR), which is in turn translocated to chromosome 9 adjacent to the remaining ABL sequences. According to the locations of the breakpoint and the size of the resulting fusion proteins, 3 sizes of proteins can be identified: a p210 BCR-ABL protein, which is regularly associated with CML; a p190 BCR-ABL protein, which is predominantly found in ALL; and a p230 BCR-ABL protein, which is found in a rare form of CML called “chronic neutrophilic leukemia” or CNL. The BCR-ABL proteins with the locations of the TKs are depicted in Fig. 8. Due to these findings, CML became the first neoplastic disease in which elucidation of pathogenesis led to a rationally designed therapy targeted at the cause of the disease. The 6-year-survival rate with imatinib in the so-called “IRIS trial”, a randomized comparison of imatinib with the former standard therapy interferon α (IFN), currently stands at 88%, with a complete cytogenetic remission rate of 82% [8]. The development of survival in CML in various trials during the years 1979-2008 is depicted in Fig. 9. Imatinib has been shown to be superior to IFN, and the survival rate with imatinib is better than with any other therapy.

2008-2-en-Hehlmann-et-al-Fig-8.jpg

2008-2-en-Hehlmann-et-al-Fig-9.jpg


The problem with current imatinib therapy is that – due to various reasons – within 6 years about 37% of patients do not respond satisfactorily or at all to imatinib, or are suspended from treatment. This is in part due to resistance mutations [9], but also to disease evolution or adverse effects. Therefore various treatment optimization trials were started to improve imatinib therapy either by combination with other agents such as IFN or araC, or by increasing the imatinib dosage. One of these studies, the German 5-arm randomized CML Study IV (GEIST), started in 2002 and has currently recruited more than 1200 patients (Fig. 10). With a survival rate of 94% in the primary imatinib arms, it is more successful than in any other current study. After 36 months, rates of major cytogenetic responses in the primary imatinib arms are close to 90%, of complete cytogenetic remissions more than 85%, and of major molecular remissions around 79%.

2008-2-en-Hehlmann-et-al-Fig-10.jpg


Once blast crisis (BC) develops, prognosis remains poor. Median survival of 605 patients with BC in the German CML Studies I, II, III and IIIA (recruitment 1983–2003) is 4 months (Fig. 11). Only 21 patients remain alive; 15 of them after transplantation.

2008-2-en-Hehlmann-et-al-Fig-11.jpg


One study of the German CML Study Group (CML-Study III) has evaluated the role of stem cell transplantation by randomized comparison with best available drug treatment [10]. After a median observation time of more than 8 years with an observation time up to 11 years, a significant survival advantage for best available drug treatment was determined (Fig. 12). It is concluded that drug treatment now should be first line therapy for CML. Stem cell transplantation remains an important second line option and may be given first line on an individual basis.

2008-2-en-Hehlmann-et-al-Fig-12.jpg


Various second line TK inhibitors are currently in various phases of evaluation. Dasatinib, which is 325 times more potent than imatinib, has been shown to have an 18-month-survival outcome of  96% in imatinib resistant or intolerant patients [11, 12]. In the chronic phase, 100 mg dasatinib once a day has been shown to be equally effective and less toxic than 2x70 mg. Dasatinib has remarkable activity in BC with a 2-year-survival of 38% in myeloid and 26% in lymphoid BC. A relevant property of dasatinib is its ability to pass the blood/brain barrier [13]. Nilotinib is about 30 times more potent than imatinib, and also has good activity in blast crisis with a 12-month-survival rate of 42% [14].

In conclusion, dasatinib and nilotinib have hematologic and cytogenetic efficacy in imatinib resistant and intolerant CML in all phases, and are active against all BCR-ABL TK-mutations except T315I. Main toxicities are cytopenias and pleural effusions (dasatinib). After dasatinib and nilotinib treatment new resistance mutations have been observed. For mutation I255V/K both drugs are not sufficiently efficacious at the standard dose, and a dose increase is recommended. In F317L, nilotinib is efficacious, in Y253H dasatinib. Agents in clinical studies include dasatinib and nilotinib in randomized evaluation for first line therapy; bosutinib, INNO406, histone deacetylase inhibitors, aurora kinase inhibitors and others, alone or in combination with other agents, in phase I and II and more in preclinical evaluation.

A major goal of the ELN is the development of guidelines for diagnosis and treatment in leukemias. CML management recommendations were published in 2006 [15], APL guidelines in 2008 [16], an update for CML is planned for 2009, and AML guidelines are in preparation. The current CML recommendations are summarized in the algorithm in Fig. 13 [17]. In case of intolerance, toxicity or pregnancy IFN is recommended, in case of imatinib failure or resistance, 2nd generation TK inhibitors or allo-SCT. In the case of suboptimal response patients should be observed closely, and an increase of imatinib dosage should be attempted. If the treatment effect is less than expected or the toxicity unusually high, compliance should be checked, interactions with other drugs or food considered and the imatinib blood levels determined. 

2008-2-en-Hehlmann-et-al-Fig-13.jpg


Challenges remaining and requiring new modes of cooperation concern geographic variations and demographics, quality controlled outcome of CML for international comparability, the availability of standardized diagnostics Europe-wide and globally, the role of TK inhibitor trough levels for response and outcome, and the provision of continued information and communication to all players in the field. In order to address these topics, a public-private partnership between the CML members of ELN and Novartis Oncology Europe has been initiated: the European Treatment and Outcome Study (EUTOS) for CML (Fig. 14).

2008-2-en-Hehlmann-et-al-Fig-14.jpg

The goals of this cooperation are expansion of the European CML registry, standardized molecular monitoring on an international basis, pharmacological monitoring and the spread of excellence. The contract was signed between the University of Heidelberg as legal representative of the ELN and Novartis in June 2007.


In summary, leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

References

1. Virchow R. Weißes Blut (Leukämie). Archiv für path Anat. 1847;1:563.

2. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497-1501.

3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-554.

4. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

5. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.

6. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996;2:561-566.

7. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.

8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

9. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.

10. Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-4692.

11. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.

12. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.

13. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.

14. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N Engl J Med. 2006;2542-2551.

15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.

16. Sanz MA, Grimwade D, Tallman MS, et al. Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;prepublished online September 23,2008.

17. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370:342-350.

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Introduction

One of the main challenges of current leukemia research is the rarity of leukemias. The incidence of the various leukemias per 100,000 population/year range between around 1 (ALL) and 3-4 (CLL). The challenge is met by collaboration within cooperative groups and networks. Integration of leukemia research in Europe has been achieved to a high degree by cooperation at the level of national leukemia study groups, notably CML study groups, and by networking on national and European levels. The German CML Study Group (founded in 1982) was one of the cofounders of the European Investigators on CML Group (EI-CML), which was initiated by S. Tura, Bologna, in 1992. Fig. 1 shows the distribution of national CML study groups in Europe. On a German level, the German CML Study Group, together with other German leukemia study groups, started the German Competence Network “Akute und chronische Leukämien” (KNL) in 1997, which was funded by the German Ministry for Education and Research in 1999. The KNL, which combines all leukemia study groups in one country and the EI-CML, which combines all European groups cooperating on one leukemia, started the European LeukemiaNet (ELN) in 2002. This has been funded by the European Commission (EC) as a Network of Excellence (NoE) from 2004 onwards. Fig. 2 shows a flow diagram of the integration of leukemia research in Europe.

2008-2-en-Hehlmann-et-al-Fig-01.jpg

2008-2-en-Hehlmann-et-al-Fig-02.jpg


The groups forming the ELN all have convincing records in promoting leukemia research and improving survival for patients with leukemia. An example is the German CML Study Group, with its 600 participants in about 300 centers (Fig. 3). The group has conducted 5 major randomized studies over the past 25 years, which has improved survival of CML patients in Germany significantly from a median survival time of 3-4 years in 1983 to an expected median of about 25 years in 2008. Fig. 4 shows the improvement of survival in the trials of the German CML Study Group up to the present time. The current 5-year-survival of 93% in CML Study IV is better than that reported by any other study group.

2008-2-en-Hehlmann-et-al-Fig-3.jpg

2008-2-en-Hehlmann-et-al-Fig-4.jpg


The ELN, representing a collaboration of European leukemia study groups and their interdisciplinary partner groups, currently comprises 147 centers in 28 countries (Fig. 5), and involves about 1,000 physicians and scientists. The participating leukemia study groups are caring for some 10,000 leukemia patients across Europe. Cooperation is amongst 95 national leukemia study groups and 102 interdisciplinary partner groups as depicted in Figs. 6 and 7.

2008-2-en-Hehlmann-et-al-Fig-5.jpg

2008-2-en-Hehlmann-et-al-Fig-6_01.jpg

2008-2-en-Hehlmann-et-al-Fig-7.jpg


The goals of the ELN are to strengthen scientific and technological excellence in research and treatment of leukemias, promote clinical trials, prepare guidelines, and spread excellence. The success of the European approach in improving research and patient outcome is well illustrated by the paradigm chronic myeloid leukemia (CML).

Paradigm CML
1847: Term “Leukämie” coined
1960: Philadelphia chromosome discovered
1985: Fusion gene BCR-ABL detected
1990: BCR-ABL induces leukemia in mice
1998: BCR-ABL TK inhibitor imatinib in phase I
2008: Median survival (expected) 25 years

The term “leukemia” was coined  in 1847 [1]  to describe patients with what was later recognized to be CML. The name was later given to the whole group of leukemias. CML became the first neoplastic disease regularly associated with a chromosomal aberration, the Philadelphia-translocation (1960) [2]. CML also became the first neoplastic disease in which the molecular pathogenesis was elucidated. In 1985, the fusion gene BCR-ABL coding for a BCR-ABL fusion tyrosine kinase (TK) was detected [3], and in 1990 it was shown that BCR-ABL can induce leukemia in mice [4, 5]. This finding prompted experiments to inhibit BCR-ABL TK via specific inhibitors [6]. In 1998, a phase I trial with the TK inhibitor imatinib was started. The outcome was striking. Even patients with advanced disease achieved cytogenetic remissions [7]. This success was achieved by the cooperation of academic research with drug development by the pharmaceutical industry. The development of a “targeted” therapy for CML would not have been possible without close cooperation among all players in the field (trial groups, groups in cytogenetic and molecular research, pharmaceutical industry, etc.)

The molecular elucidation of CML pathogenesis relied heavily on earlier research with retroviruses and oncogenes. In this research an acute leukemia-inducing murine retrovirus, termed Abelson Virus, was found to contain a 5.6 kb long cellular RNA-sequence which, due to its oncogenic potential, was termed an “ABL oncogene”. In the human genome, ABL is located on chromosome 9, from where part of it is translocated to chromosome 22 in exchange for a larger piece of chromosome 22 called the “breakpoint cluster region” (BCR), which is in turn translocated to chromosome 9 adjacent to the remaining ABL sequences. According to the locations of the breakpoint and the size of the resulting fusion proteins, 3 sizes of proteins can be identified: a p210 BCR-ABL protein, which is regularly associated with CML; a p190 BCR-ABL protein, which is predominantly found in ALL; and a p230 BCR-ABL protein, which is found in a rare form of CML called “chronic neutrophilic leukemia” or CNL. The BCR-ABL proteins with the locations of the TKs are depicted in Fig. 8. Due to these findings, CML became the first neoplastic disease in which elucidation of pathogenesis led to a rationally designed therapy targeted at the cause of the disease. The 6-year-survival rate with imatinib in the so-called “IRIS trial”, a randomized comparison of imatinib with the former standard therapy interferon α (IFN), currently stands at 88%, with a complete cytogenetic remission rate of 82% [8]. The development of survival in CML in various trials during the years 1979-2008 is depicted in Fig. 9. Imatinib has been shown to be superior to IFN, and the survival rate with imatinib is better than with any other therapy.

2008-2-en-Hehlmann-et-al-Fig-8.jpg

2008-2-en-Hehlmann-et-al-Fig-9.jpg


The problem with current imatinib therapy is that – due to various reasons – within 6 years about 37% of patients do not respond satisfactorily or at all to imatinib, or are suspended from treatment. This is in part due to resistance mutations [9], but also to disease evolution or adverse effects. Therefore various treatment optimization trials were started to improve imatinib therapy either by combination with other agents such as IFN or araC, or by increasing the imatinib dosage. One of these studies, the German 5-arm randomized CML Study IV (GEIST), started in 2002 and has currently recruited more than 1200 patients (Fig. 10). With a survival rate of 94% in the primary imatinib arms, it is more successful than in any other current study. After 36 months, rates of major cytogenetic responses in the primary imatinib arms are close to 90%, of complete cytogenetic remissions more than 85%, and of major molecular remissions around 79%.

2008-2-en-Hehlmann-et-al-Fig-10.jpg


Once blast crisis (BC) develops, prognosis remains poor. Median survival of 605 patients with BC in the German CML Studies I, II, III and IIIA (recruitment 1983–2003) is 4 months (Fig. 11). Only 21 patients remain alive; 15 of them after transplantation.

2008-2-en-Hehlmann-et-al-Fig-11.jpg


One study of the German CML Study Group (CML-Study III) has evaluated the role of stem cell transplantation by randomized comparison with best available drug treatment [10]. After a median observation time of more than 8 years with an observation time up to 11 years, a significant survival advantage for best available drug treatment was determined (Fig. 12). It is concluded that drug treatment now should be first line therapy for CML. Stem cell transplantation remains an important second line option and may be given first line on an individual basis.

2008-2-en-Hehlmann-et-al-Fig-12.jpg


Various second line TK inhibitors are currently in various phases of evaluation. Dasatinib, which is 325 times more potent than imatinib, has been shown to have an 18-month-survival outcome of  96% in imatinib resistant or intolerant patients [11, 12]. In the chronic phase, 100 mg dasatinib once a day has been shown to be equally effective and less toxic than 2x70 mg. Dasatinib has remarkable activity in BC with a 2-year-survival of 38% in myeloid and 26% in lymphoid BC. A relevant property of dasatinib is its ability to pass the blood/brain barrier [13]. Nilotinib is about 30 times more potent than imatinib, and also has good activity in blast crisis with a 12-month-survival rate of 42% [14].

In conclusion, dasatinib and nilotinib have hematologic and cytogenetic efficacy in imatinib resistant and intolerant CML in all phases, and are active against all BCR-ABL TK-mutations except T315I. Main toxicities are cytopenias and pleural effusions (dasatinib). After dasatinib and nilotinib treatment new resistance mutations have been observed. For mutation I255V/K both drugs are not sufficiently efficacious at the standard dose, and a dose increase is recommended. In F317L, nilotinib is efficacious, in Y253H dasatinib. Agents in clinical studies include dasatinib and nilotinib in randomized evaluation for first line therapy; bosutinib, INNO406, histone deacetylase inhibitors, aurora kinase inhibitors and others, alone or in combination with other agents, in phase I and II and more in preclinical evaluation.

A major goal of the ELN is the development of guidelines for diagnosis and treatment in leukemias. CML management recommendations were published in 2006 [15], APL guidelines in 2008 [16], an update for CML is planned for 2009, and AML guidelines are in preparation. The current CML recommendations are summarized in the algorithm in Fig. 13 [17]. In case of intolerance, toxicity or pregnancy IFN is recommended, in case of imatinib failure or resistance, 2nd generation TK inhibitors or allo-SCT. In the case of suboptimal response patients should be observed closely, and an increase of imatinib dosage should be attempted. If the treatment effect is less than expected or the toxicity unusually high, compliance should be checked, interactions with other drugs or food considered and the imatinib blood levels determined. 

2008-2-en-Hehlmann-et-al-Fig-13.jpg


Challenges remaining and requiring new modes of cooperation concern geographic variations and demographics, quality controlled outcome of CML for international comparability, the availability of standardized diagnostics Europe-wide and globally, the role of TK inhibitor trough levels for response and outcome, and the provision of continued information and communication to all players in the field. In order to address these topics, a public-private partnership between the CML members of ELN and Novartis Oncology Europe has been initiated: the European Treatment and Outcome Study (EUTOS) for CML (Fig. 14).

2008-2-en-Hehlmann-et-al-Fig-14.jpg

The goals of this cooperation are expansion of the European CML registry, standardized molecular monitoring on an international basis, pharmacological monitoring and the spread of excellence. The contract was signed between the University of Heidelberg as legal representative of the ELN and Novartis in June 2007.


In summary, leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

References

1. Virchow R. Weißes Blut (Leukämie). Archiv für path Anat. 1847;1:563.

2. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497-1501.

3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-554.

4. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

5. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.

6. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996;2:561-566.

7. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.

8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

9. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.

10. Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-4692.

11. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.

12. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.

13. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.

14. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N Engl J Med. 2006;2542-2551.

15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.

16. Sanz MA, Grimwade D, Tallman MS, et al. Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;prepublished online September 23,2008.

17. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370:342-350.

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Хельман Р., Саусселе С.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12401" ["VALUE"]=> array(2) { ["TEXT"]=> string(488) "<p>В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12377" ["VALUE"]=> string(29) "10.3205/ctt-2008-en-000015.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2008-en-000015.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12420" ["VALUE"]=> array(2) { ["TEXT"]=> string(90) "<p class="Autor">R. Hehlmann, S. Saußele<p class="Autor">" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(58) "

R. Hehlmann, S. Saußele

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12422" ["VALUE"]=> array(2) { ["TEXT"]=> string(736) "<p>Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.</p> <p class="bodytext">Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(702) "

Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12378" ["VALUE"]=> string(60) "Integration of leukemia research in Europe: the paradigm CML" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(60) "Integration of leukemia research in Europe: the paradigm CML" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12389" ["VALUE"]=> array(2) { ["TEXT"]=> string(8845) "<p class="bodytext"> Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8305) "

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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R. Hehlmann, S. Saußele

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Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

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Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

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Хельман Р., Саусселе С.

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string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12374" ["VALUE"]=> string(2) "87" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(2) "87" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(59) "Rüdiger Hehlmann" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12401" ["VALUE"]=> array(2) { ["TEXT"]=> string(488) "<p>В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12389" ["VALUE"]=> array(2) { ["TEXT"]=> string(8845) "<p class="bodytext"> Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8305) "

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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Review articles

Advances in T cell receptor gene transfer for immunotherapy

Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

Generation of regulatory T cells by T cell receptor gene transfer

Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

Review articles

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Advances in T cell receptor gene transfer for immunotherapy

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

Department of Immunology, Royal Free Hospital, University College London, UK

Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

Review articles

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12347 [VALUE] => Array ( [TEXT] => <p class="bodytext">Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Generation of regulatory T cells by T cell receptor gene transfer

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

Department of Immunology, Royal Free Hospital, University College London, UK

Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

Review articles

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Хельман Р., Саусселе С.

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В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

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R. Hehlmann, S. Saußele

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12421 [VALUE] => Array ( [TEXT] => <p>Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

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Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

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В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
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Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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Integration of leukemia research in Europe: the paradigm CML

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R. Hehlmann, S. Saußele

Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.