Autoimmunity and Immunotherapy for Cancer
http://www.100md.com
《新英格兰医药杂志》
Adjuvant treatment for patients after resection of high-risk and regionally metastatic melanoma remains suboptimal. Despite the Food and Drug Administration's approval of high-dose interferon alfa-2b, the substantial toxicity of the therapy and the fact that its benefit is limited to 20 to 30 percent of patients at risk have hindered its general acceptance.
Attempts to identify patients who benefit from adjuvant treatment with interferon alfa-2b have been disappointing to date. Although analyses of individual studies suggest that the benefit of high-dose interferon alfa-2b might be restricted to certain subgroups of patients, on the basis of the number of melanoma-involved lymph nodes, no consistent overall pattern was observed. In addition, no other features have been identified that predict either responsiveness of the tumor among patients with advanced melanoma or the likelihood of freedom from relapse in the adjuvant setting among patients who receive interferon alfa-2b. Consequently, adjuvant treatment with this agent has been proposed for all patients with intermediate- and high-risk melanoma for whom the likelihood of reducing the risk of relapse outweighs the anticipated toxic effects of the treatment.1
The principal mechanism underlying the beneficial effect of interferon alfa-2b in patients with melanoma is unclear. Proposed mechanisms include enhanced antigen presentation as a result of the up-regulation of the expression of major-histocompatibility-complex molecules, promotion of dendritic-cell development, increases in the function of immune effector cells, antiangiogenic effects, and direct antiproliferative effects on the tumor. In this issue of the Journal, Gogas et al. report a strong association between the development of autoimmunity during or after treatment with adjuvant interferon alfa-2b and a favorable outcome in patients with high-risk melanoma.2 The results of this prospective trial suggest a mechanistic connection between autoimmunity and the benefit from interferon alfa-2b in patients with melanoma.
The link between type 1 interferons, which include interferon alfa-2b, and autoimmunity is well established. Autoimmune disorders, including thyroiditis and vitiligo, have been reported to develop in 15 to 30 percent of patients who receive interferon alfa therapy. Patients with systemic lupus erythematosus have elevated levels of interferon alfa, and their lymphocytes have a gene-expression signature that is indicative of activation of the interferon gene.3 In mouse models of systemic lupus erythematosus, lupus does not develop as frequently or as rapidly in mice that lack the type 1 interferon receptor as it does in mice that have the receptor.3 Similar mouse genetic models suggest that the interferons have a role in type 1 diabetes mellitus and other autoimmune conditions.
Given the ability of type 1 interferons to induce an immune response against autoantigens, it is not surprising that they also have a role in inducing an immune response against tumors. An association between autoimmunity and a favorable antitumor effect has been reported for several forms of immunotherapy, particularly in patients with melanoma. The development of autoimmune thyroid disease in patients treated with interleukin-2, first reported in 1988,4 has been confirmed by many groups. Others have reported the development of arthritis, insulin autoantibodies, vasculitis, vitiligo, and inflammatory bowel disease as a result of this treatment.5 Although reports of an association between thyroid dysfunction resulting from treatment with interleukin-2 and tumor regression have been inconsistent, this association has usually been noted when the analysis was confined to patients who had thyroid autoantibodies. The blockade of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T-cell function, by an anti–CTLA-4 antibody has also been reported to cause autoimmune disorders in patients with cancer, which appear to be strongly associated with tumor regression.6
Gogas et al. provide the strongest data to date connecting the development of autoimmunity with a favorable antitumor effect of immunotherapy. Although their data do not exclude the possibility that patients with high-risk melanoma in whom evidence of autoimmunity develops as a result of interferon alfa-2b therapy have a better prognosis even in the absence of therapy, this explanation seems unlikely because these patients had disease progression immediately before initiation of therapy. In fact, the results of the study by Gogas et al. appear even more robust than would be predicted from the retrospective analyses of patients receiving immunotherapy for advanced cancer. The authors found that the development of autoimmunity was associated with an approximate reduction by a factor of 50 in the risk of recurrence of melanoma. Considering that a substantial proportion of the patients in whom autoimmunity did not develop in the study by Gogas et al. would have remained free of relapse with surgery alone, this finding suggests that most of the benefit of interferon alfa-2b is restricted to patients in whom evidence of autoimmunity appears.
The observations of Gogas et al. shed considerable light on the mechanism of action of interferon alfa-2b, and possibly of immunotherapy in general, in patients with melanoma. The observations fall short, however, of providing a biomarker that would be predictive of the benefit of interferon alfa-2b. Because autoimmunity was observed only after a median of three months — and in some instances, more than a year — from the start of interferon alfa-2b therapy, the development of autoimmunity cannot be used as a criterion for selecting patients for the therapy.6 Nonetheless, patients with a documented preexisting propensity toward autoimmunity might be a group for whom immunotherapy should be considered, providing that the resulting autoimmunity could be anticipated to be managed effectively.
A clearer understanding of which patients are predisposed to autoimmunity induced by interferon alfa might help identify biomarkers that predict clinical benefit from therapy with this cytokine. The well-known association between the HLA genotype and certain autoimmune diseases might give clues to the identification of such a biomarker. In addition, polymorphisms in the CTLA-4 gene7 and mutations in the FOXP3 transcription factor, critical regulatory pathways in T cells, have been reported to be associated with an inherited syndrome characterized by autoimmune thyroid disease and diabetes, among other disorders.8 Whether relative deficiencies in these regulatory pathways play a role in either the autoimmunity or the antitumor effects found with interferon alfa remains to be determined. Although better identification of the population predisposed to autoimmunity might help clinicians select patients for immunotherapy, it remains unclear to what extent new treatments that increase the likelihood of autoimmunity will improve immunotherapy for cancer. In any event, the results of the study by Gogas et al. clearly call for closer collaborations between investigators in the fields of immunotherapy for cancer and autoimmunity to address some of these critical issues better.
Interferon alfa and other forms of immunotherapy have been shown to induce autoimmunity, particularly thyroid dysfunction, in patients with tumors other than melanomas and in numbers similar to those reported by Gogas et al. Yet an association between the development of autoimmunity and responsiveness to immunotherapy has largely been restricted to melanoma and renal cancer. In patients with renal cancer, the expression of carbonic anhydrase IX predicts the responsiveness to immunotherapy with interleukin-2,9 and the expression of B7-H1, a molecule associated with immune suppression, by a tumor can predict poor survival after nephrectomy.10 Results of several recent studies suggest that melanomas can be divided into distinct subgroups on the basis of the genes they express.11 Although the extent to which these subgroups might vary in sensitivity to immunotherapy remains to be established, their existence underscores the potential for information useful to treatment selection to be gleaned from further investigation of the tumor itself.
The work by Gogas et al. and others suggests that there exists a population of patients with diminished immune regulation in whom autoimmunity develops during effective immunotherapy, such as with interferon alfa. If such patients have immune-sensitive tumors (which may include a yet-to-be-defined subgroup of melanomas), they would be able to mount a protective antitumor immune response. The prospective identification of such patients not only will help clinicians select patients for immunotherapy but also will spare other patients from exposure to the side effects of ineffective treatment. This work not only could lead to improved treatment strategies but also may move clinicians toward the desired goal of personalized therapy for patients with melanoma.
Dr. Koon reports having received grant support from Novartis. No other potential conflict of interest relevant to this article was reported.
Source Information
From Beth Israel Deaconess Medical Center, Boston.
References
Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004;351:998-1012.
Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006;354:709-718.
Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 2005;23:307-336.
Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988;318:1557-1563.
Atkins MB. Autoimmune disorders induced by interleukin-2 therapy. In: Atkins MB, Mier JW, eds. Therapeutic applications of interleukin-2. New York: Marcel Dekker, 1993:389-408.
Ribas A, Camacho LH, Lopez-Berenstein G, et al. Antitumor activity in melanoma and anti-self responses in a phase 1 trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23:8968-8977.
Kristiansen OP, Larsen ZM, Pociot F. CTLA-4 in autoimmune diseases -- a general susceptibility gene to autoimmunity? Genes Immun 2000;1:170-184.
Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003;15:430-435.
Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005;11:3714-3721.
Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004;101:17174-17179.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-2147.(Henry Koon, M.D., and Mic)
Attempts to identify patients who benefit from adjuvant treatment with interferon alfa-2b have been disappointing to date. Although analyses of individual studies suggest that the benefit of high-dose interferon alfa-2b might be restricted to certain subgroups of patients, on the basis of the number of melanoma-involved lymph nodes, no consistent overall pattern was observed. In addition, no other features have been identified that predict either responsiveness of the tumor among patients with advanced melanoma or the likelihood of freedom from relapse in the adjuvant setting among patients who receive interferon alfa-2b. Consequently, adjuvant treatment with this agent has been proposed for all patients with intermediate- and high-risk melanoma for whom the likelihood of reducing the risk of relapse outweighs the anticipated toxic effects of the treatment.1
The principal mechanism underlying the beneficial effect of interferon alfa-2b in patients with melanoma is unclear. Proposed mechanisms include enhanced antigen presentation as a result of the up-regulation of the expression of major-histocompatibility-complex molecules, promotion of dendritic-cell development, increases in the function of immune effector cells, antiangiogenic effects, and direct antiproliferative effects on the tumor. In this issue of the Journal, Gogas et al. report a strong association between the development of autoimmunity during or after treatment with adjuvant interferon alfa-2b and a favorable outcome in patients with high-risk melanoma.2 The results of this prospective trial suggest a mechanistic connection between autoimmunity and the benefit from interferon alfa-2b in patients with melanoma.
The link between type 1 interferons, which include interferon alfa-2b, and autoimmunity is well established. Autoimmune disorders, including thyroiditis and vitiligo, have been reported to develop in 15 to 30 percent of patients who receive interferon alfa therapy. Patients with systemic lupus erythematosus have elevated levels of interferon alfa, and their lymphocytes have a gene-expression signature that is indicative of activation of the interferon gene.3 In mouse models of systemic lupus erythematosus, lupus does not develop as frequently or as rapidly in mice that lack the type 1 interferon receptor as it does in mice that have the receptor.3 Similar mouse genetic models suggest that the interferons have a role in type 1 diabetes mellitus and other autoimmune conditions.
Given the ability of type 1 interferons to induce an immune response against autoantigens, it is not surprising that they also have a role in inducing an immune response against tumors. An association between autoimmunity and a favorable antitumor effect has been reported for several forms of immunotherapy, particularly in patients with melanoma. The development of autoimmune thyroid disease in patients treated with interleukin-2, first reported in 1988,4 has been confirmed by many groups. Others have reported the development of arthritis, insulin autoantibodies, vasculitis, vitiligo, and inflammatory bowel disease as a result of this treatment.5 Although reports of an association between thyroid dysfunction resulting from treatment with interleukin-2 and tumor regression have been inconsistent, this association has usually been noted when the analysis was confined to patients who had thyroid autoantibodies. The blockade of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), a negative regulator of T-cell function, by an anti–CTLA-4 antibody has also been reported to cause autoimmune disorders in patients with cancer, which appear to be strongly associated with tumor regression.6
Gogas et al. provide the strongest data to date connecting the development of autoimmunity with a favorable antitumor effect of immunotherapy. Although their data do not exclude the possibility that patients with high-risk melanoma in whom evidence of autoimmunity develops as a result of interferon alfa-2b therapy have a better prognosis even in the absence of therapy, this explanation seems unlikely because these patients had disease progression immediately before initiation of therapy. In fact, the results of the study by Gogas et al. appear even more robust than would be predicted from the retrospective analyses of patients receiving immunotherapy for advanced cancer. The authors found that the development of autoimmunity was associated with an approximate reduction by a factor of 50 in the risk of recurrence of melanoma. Considering that a substantial proportion of the patients in whom autoimmunity did not develop in the study by Gogas et al. would have remained free of relapse with surgery alone, this finding suggests that most of the benefit of interferon alfa-2b is restricted to patients in whom evidence of autoimmunity appears.
The observations of Gogas et al. shed considerable light on the mechanism of action of interferon alfa-2b, and possibly of immunotherapy in general, in patients with melanoma. The observations fall short, however, of providing a biomarker that would be predictive of the benefit of interferon alfa-2b. Because autoimmunity was observed only after a median of three months — and in some instances, more than a year — from the start of interferon alfa-2b therapy, the development of autoimmunity cannot be used as a criterion for selecting patients for the therapy.6 Nonetheless, patients with a documented preexisting propensity toward autoimmunity might be a group for whom immunotherapy should be considered, providing that the resulting autoimmunity could be anticipated to be managed effectively.
A clearer understanding of which patients are predisposed to autoimmunity induced by interferon alfa might help identify biomarkers that predict clinical benefit from therapy with this cytokine. The well-known association between the HLA genotype and certain autoimmune diseases might give clues to the identification of such a biomarker. In addition, polymorphisms in the CTLA-4 gene7 and mutations in the FOXP3 transcription factor, critical regulatory pathways in T cells, have been reported to be associated with an inherited syndrome characterized by autoimmune thyroid disease and diabetes, among other disorders.8 Whether relative deficiencies in these regulatory pathways play a role in either the autoimmunity or the antitumor effects found with interferon alfa remains to be determined. Although better identification of the population predisposed to autoimmunity might help clinicians select patients for immunotherapy, it remains unclear to what extent new treatments that increase the likelihood of autoimmunity will improve immunotherapy for cancer. In any event, the results of the study by Gogas et al. clearly call for closer collaborations between investigators in the fields of immunotherapy for cancer and autoimmunity to address some of these critical issues better.
Interferon alfa and other forms of immunotherapy have been shown to induce autoimmunity, particularly thyroid dysfunction, in patients with tumors other than melanomas and in numbers similar to those reported by Gogas et al. Yet an association between the development of autoimmunity and responsiveness to immunotherapy has largely been restricted to melanoma and renal cancer. In patients with renal cancer, the expression of carbonic anhydrase IX predicts the responsiveness to immunotherapy with interleukin-2,9 and the expression of B7-H1, a molecule associated with immune suppression, by a tumor can predict poor survival after nephrectomy.10 Results of several recent studies suggest that melanomas can be divided into distinct subgroups on the basis of the genes they express.11 Although the extent to which these subgroups might vary in sensitivity to immunotherapy remains to be established, their existence underscores the potential for information useful to treatment selection to be gleaned from further investigation of the tumor itself.
The work by Gogas et al. and others suggests that there exists a population of patients with diminished immune regulation in whom autoimmunity develops during effective immunotherapy, such as with interferon alfa. If such patients have immune-sensitive tumors (which may include a yet-to-be-defined subgroup of melanomas), they would be able to mount a protective antitumor immune response. The prospective identification of such patients not only will help clinicians select patients for immunotherapy but also will spare other patients from exposure to the side effects of ineffective treatment. This work not only could lead to improved treatment strategies but also may move clinicians toward the desired goal of personalized therapy for patients with melanoma.
Dr. Koon reports having received grant support from Novartis. No other potential conflict of interest relevant to this article was reported.
Source Information
From Beth Israel Deaconess Medical Center, Boston.
References
Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med 2004;351:998-1012.
Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006;354:709-718.
Theofilopoulos AN, Baccala R, Beutler B, Kono DH. Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 2005;23:307-336.
Atkins MB, Mier JW, Parkinson DR, Gould JA, Berkman EM, Kaplan MM. Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 1988;318:1557-1563.
Atkins MB. Autoimmune disorders induced by interleukin-2 therapy. In: Atkins MB, Mier JW, eds. Therapeutic applications of interleukin-2. New York: Marcel Dekker, 1993:389-408.
Ribas A, Camacho LH, Lopez-Berenstein G, et al. Antitumor activity in melanoma and anti-self responses in a phase 1 trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 2005;23:8968-8977.
Kristiansen OP, Larsen ZM, Pociot F. CTLA-4 in autoimmune diseases -- a general susceptibility gene to autoimmunity? Genes Immun 2000;1:170-184.
Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003;15:430-435.
Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005;11:3714-3721.
Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 2004;101:17174-17179.
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-2147.(Henry Koon, M.D., and Mic)