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Преодоление иммунной толерантности как способ лечения злокачественных опухолей: новые перспективы
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Аннотация
В настоящем обзоре литературы изложены современные представления о механизмах противоопухолевого иммунитета, а также роли одного из классов новых иммуномодуляторов – блокаторов иммунных регуляторных молекул CTLA4, которые в ближайшее время могут оказаться в арсенале практикующих онкологов России и уже с успехом применяются для лечения диссеминированной меланомы кожи в странах Европы и США. Ипилимумаб – первый препарат, представитель класса, зарегистрированный по данному показанию в странах Европы и США. Принципиально отличающийся от цитостатических препаратов механизм действия обусловливает необходимость других подходов к оценке объективного ответа на лечение и особого внимания к разнообразным, иногда неожиданным для химиотерапевтов побочным реакциям.
Ключевые слова: иммуноонкология, анти-CTLA4, анти-PD1, противоопухолевый иммунитет, ипилимумаб, меланома кожи.
Ключевые слова: иммуноонкология, анти-CTLA4, анти-PD1, противоопухолевый иммунитет, ипилимумаб, меланома кожи.
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This literature review outlines the current knowledge of the mechanisms of antitumor immunity and the role of one of the new classes of immunomodulators blocking immune regulatory molecules CTLA4, which soon could be used by oncology practitioners in Russia and has already been successfully used for the treatment of disseminated melanoma in Europe and the United States. Ipilimumab is the first drug, which represent the class registered on this indication in Europe and the United States. Fundamentally different mode of action from the cytostatic drugs mode of action is required to find another approach to assessing an objective response to treatment and special attention to the different, sometimes unexpected side effects of chemotherapy.
Key words: immuno-oncology, anti-CTLA4, anti-PD1, antitumor immunity, Ipilimumab, cutaneous melanoma.
Полный текст
Список литературы
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7. Dariavach P et al. Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 1988; 18 (12): 1901–5.
8. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19 (19): 5300–9.
9. Matzinger P. An innate sense of danger. Ann N Y Acad Sci 2002; 961: 341–2.
10. Ribas A, Butterfield LH, Economou JS. Genetic immunotherapy for cancer. Oncologist 2000; 5 (2): 87–98.
11. Van Wijk F et al. The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins. J Immunol 2007; 178 (11): 6894–900.
12. Reuben JM et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer 2006; 106 (11): 2437–44.
13. Ribas A et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013; 31 (5): 616–22.
14. Pfizer stops Ph III trial of single-agent tremelimumab in advanced melanoma. 07.04.2008; 24.11.2013. Available from: http://www.thepharmaletter.com/article/pfizer-stops-ph-iii-trial-of-single-agent-tremelimumab-in-adv....
15. Wilson KS, Kotb R. Is tremelimumab beneficial in advanced melanoma? J Clin Oncol 2013. 31 (22): 2835–6.
16. Hodi FS et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (8): 711–23.
17. Robert C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364 (26): 2517–26.
18. Wolchok JD et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15 (23): 7412–20.
19. McDermott D et al. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol 2013; 24 (10): 2694–8.
20. Maio M. Survival amalysis with 5 years of follow up in phase III study of ipilimumab and dacarbazine in metastatic melanoma: ESMO oral presentation 3704. Eur J Cancer 2013.
21. Wolchok JD et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol 2013; 24 (8): 2174–80.
22. Sherrill B et al. Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma. Br J Cancer 2013; 109 (1): 8–13.
23. Gilardi L et al. Ipilimumab-Induced Immunomediated Adverse Events: Possible Pitfalls in 18F-FDG PET/CT Interpretation. Clin Nucl Med 2013.
24. Kaehler KC et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol 2010; 37 (5): 485–98.
25. Delyon J et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013; 24 (6): 1697–703.
26. Di Giacomo AM et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 2013; 62 (6): 1021–8.
27. Holmgaard RB et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 2013; 210 (7): 1389–402.
28. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol 2008; 8 (1): 74–80.
29. Weber JS et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013; 119 (9): 1675–82.
30. Hamid O et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369 (2): 134–44.
31. Wolchok JD et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369 (2): 122–33.
32. Hodi FS, Powels T, Cassier P. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC). Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Ann Oncol: p. Poster 879 ESMO 2013.
33. GM-CSF/Ipilimumab combination extends melanoma survival. Cancer Discov 2013; 3 (7): OF6.
34. Rosenblatt J et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 2011; 34 (5): 409–18.
35. Wehler TC et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007; 109 (1): 365–73.
36. Rosenberg SA et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17 (13): 4550–7.
2. Villasor RP, Fetalino MS, Ramirez AT. The Clinical Use of Bcg Vaccine in Stimulating Host Resistance to Cancer. Philipp J Surg Surg Spec 1963; 18: 85–93.
3. Robinson MR. BCG in the management of superficial bladder cancer. Prog Clin Biol Res 1985; 185B: 161–6.
4. Burnet M. Cancer; a biological approach. I. The processes of control. Br Med J 1957; 1 (5022): 779–86.
5. Dunn GP et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3 (11): 991–8.
6. Vesely MD, Schreiber RD. Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci 2013; 1284: 1–5.
7. Dariavach P et al. Human Ig superfamily CTLA-4 gene: chromosomal localization and identity of protein sequence between murine and human CTLA-4 cytoplasmic domains. Eur J Immunol 1988; 18 (12): 1901–5.
8. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19 (19): 5300–9.
9. Matzinger P. An innate sense of danger. Ann N Y Acad Sci 2002; 961: 341–2.
10. Ribas A, Butterfield LH, Economou JS. Genetic immunotherapy for cancer. Oncologist 2000; 5 (2): 87–98.
11. Van Wijk F et al. The CD28/CTLA-4-B7 signaling pathway is involved in both allergic sensitization and tolerance induction to orally administered peanut proteins. J Immunol 2007; 178 (11): 6894–900.
12. Reuben JM et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer 2006; 106 (11): 2437–44.
13. Ribas A et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013; 31 (5): 616–22.
14. Pfizer stops Ph III trial of single-agent tremelimumab in advanced melanoma. 07.04.2008; 24.11.2013. Available from: http://www.thepharmaletter.com/article/pfizer-stops-ph-iii-trial-of-single-agent-tremelimumab-in-adv....
15. Wilson KS, Kotb R. Is tremelimumab beneficial in advanced melanoma? J Clin Oncol 2013. 31 (22): 2835–6.
16. Hodi FS et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (8): 711–23.
17. Robert C et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; 364 (26): 2517–26.
18. Wolchok JD et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15 (23): 7412–20.
19. McDermott D et al. Efficacy and safety of ipilimumab in metastatic melanoma patients surviving more than 2 years following treatment in a phase III trial (MDX010-20). Ann Oncol 2013; 24 (10): 2694–8.
20. Maio M. Survival amalysis with 5 years of follow up in phase III study of ipilimumab and dacarbazine in metastatic melanoma: ESMO oral presentation 3704. Eur J Cancer 2013.
21. Wolchok JD et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol 2013; 24 (8): 2174–80.
22. Sherrill B et al. Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma. Br J Cancer 2013; 109 (1): 8–13.
23. Gilardi L et al. Ipilimumab-Induced Immunomediated Adverse Events: Possible Pitfalls in 18F-FDG PET/CT Interpretation. Clin Nucl Med 2013.
24. Kaehler KC et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol 2010; 37 (5): 485–98.
25. Delyon J et al. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013; 24 (6): 1697–703.
26. Di Giacomo AM et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 2013; 62 (6): 1021–8.
27. Holmgaard RB et al. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med 2013; 210 (7): 1389–402.
28. Mellor AL, Munn DH. Creating immune privilege: active local suppression that benefits friends, but protects foes. Nat Rev Immunol 2008; 8 (1): 74–80.
29. Weber JS et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013; 119 (9): 1675–82.
30. Hamid O et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369 (2): 134–44.
31. Wolchok JD et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369 (2): 122–33.
32. Hodi FS, Powels T, Cassier P. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC). Additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Ann Oncol: p. Poster 879 ESMO 2013.
33. GM-CSF/Ipilimumab combination extends melanoma survival. Cancer Discov 2013; 3 (7): OF6.
34. Rosenblatt J et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother 2011; 34 (5): 409–18.
35. Wehler TC et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007; 109 (1): 365–73.
36. Rosenberg SA et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17 (13): 4550–7.
Авторы
И.В.Самойленко, Г.Ю.Харкевич, Л.В.Демидов
Отделение биотерапии опухолей ФГБУ РОНЦ им. Н.Н.Блохина РАМН, Москва
Отделение биотерапии опухолей ФГБУ РОНЦ им. Н.Н.Блохина РАМН, Москва
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I.V.Samoilenko, G.U.Kharkevich, L.V.Demidov
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