Эффективность иммунотерапии при разных злокачественных новообразованиях: обзор литературы

Известно, что иммунная система играет одну из основных ролей в развитии онкологии. Это подтверждается и тем, что пациенты с врожденным или приобретенным иммунодефицитом имеют более высокие риски развития рака. На сегодняшний день выделяют несколько видов иммунотерапии, каждый из которых имеет свой механизм действия. В этом обзоре представлены данные клинических исследований основных вариантов лечения, в основе которых лежат механизмы иммунотерапии, такие как клеточная иммунотерапия, применение антител и цитокинов, комбинированная иммунотерапия (с использованием чекпойнт-ингибиторов). Приведенные сведения свидетельствуют о положительной тенденции этого способа лечения у больных с онкологическими заболеваниями.

1. Oiseth S.J., Aziz M.S. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat 2017;3(10):250–61. DOI: 10.20517/23944722.2017.41.

2. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berl Klin Wochenschr 1868;5:137.

3. Fehleisen F. Ueber die Züchtung der Erysipelkokken auf künstlichem Nährboden und ihre Übertragbarkeit auf den Menschen. Dtsch Med Wochenschr. 1882;8(31):553–4.

4. Coley W.B. II. Contribution to the knowledge of sarcoma. Annals of surgery 1891;14(3):199.

5. Пронько Д. Прицел на раковые мишени. Наука и инновации 2017;3(169):29–31.

6. Old L.J., Clarke D.A.,Benacerraf B. Effect of Bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature 1959;184(4682):291–2. DOI: 10.1038/184291a0.

7. Morales A., Eidinger D., Bruce A. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976;116(2):180–2. DOI: 10.1016/S0022-5347(17)58737-6.

8. Dock G. The influence of complicating diseases upon leukaemia. The American J Med Sci (1827–1924) 1904;127(4):563.

9. Kelly E., Russell S.J. History of oncolytic viruses: genesis to genetic engineering. Mol Ther 2007;15(4):651–9. DOI: 10.1038/sj.mt.6300108.

10. Ring C.J. Cytolytic viruses as potential anticancer agents. J Gen Virol 2002;83(3):491–502. DOI: https://doi.org/10.1099/00221317-83-3-491.

11. Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 2015;125(9):3335–7. DOI: 10.1172/JCI83871.

12. Korneev K.V., Atretkhany K.-S.N., Drutskaya M.S. et al. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis. Cytokine 2017;89(1):127–35. DOI: 10.1016/j.cyto.2016.01.021.

13. Kranz L.M., Diken M., Haas H., et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 2016;534(7607):396–401. DOI: 10.1038/nature18300.

14. Riddell S.R. Progress in cancer vaccines by enhanced self-presentation. Procof Natl Acad Sci USA 2001;98(16):8933–5. DOI: 10.1073/pnas.171326398.

15. Kroemer G., Galluzzi L., Kepp O., Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31(1):51–72. DOI: 10.1146/annurev-immunol-032712-100008.

16. Apetoh L., Ghiringhelli F., Tesniere A. et al. The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy. Immunol Rev2007;220(1):47–59. DOI: 10.1111/j.1600-065X.2007.00573.x.

17. Tabi Z., Spary L.K., Coleman S. et al. Resistance of CD45RA− T cells to apoptosis and functional impairment, and activation of tumor-antigen specific T Cells during radiation therapy of prostate cancer. J Immunol 2010;185(2):1330–9. DOI: 10.4049/jimmunol.1000488.

18. Hirayama M., Nishimura Y. The present status and future prospects of peptide-based cancer vaccines. International immunology 2016;28(7):319–28. DOI: 10.1093/intimm/dxw027.

19. Dastmalchi F., Karachi A., Mitchell D., Rahman M. Dendritic Cell therapy eLS 2018;1(1):1–27. DOI: 10.1002/9780470015902.a0024243.

20. Jensen T.I., Axelgaard E., Bak R.O. Therapeutic gene editing in haematological disorders with CRISPR/Cas9. British J Haematol 2019;185(5):821–35. DOI: 10.1111/bjh.15851.

21. Киселевский М.В., Чикилева И.О., Ситдикова С.М. и др. Перспективы применения генетически модифицированных лимфоцитов с химерным Т-клеточным рецептором (CAR-T-клеток) для терапии солидных опухолей. Иммунология 2019;40(4):48–55. DOI: 10.24411/0206-4952-2019-14006.

22. Schultz L., Mackall C. Driving CAR T cell translation forward. Sci Transl Med 2019;11(481):eaaw2127. DOI: 10.1126/scitranslmed.aaw2127.

23. Maus M.V., Haas A.R., Beatty G.L. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res 2013;1(1):26–31. DOI: 10.1158/2326-6066.CIR-13-0006.

24. Ryman J.T., Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT Pharmacometrics Syst Pharmacol 2017;6(9):576–88. DOI: 10.1002/psp4.12224.

25. Scott A.M., Wolchok J.D., Old L.J. Antibody therapy of cancer. Nat Rev Cancer 2012;12(4):278–87. DOI: 10.1038/nrc3236.

26. Weiner L.M., Surana R., Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol 2010;10(5):317–27. DOI: 10.1038/nri2744.

27. Seidel U.J.E., Schlegel P., Lang P. Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Frontiers in immunology 2013;4(76):1–8. DOI: 10.3389/fimmu.2013.00076.

28. Lee S., Margolin K., Cytokines in cancer immunotherapy. Cancers 2011;3(4):3856–93. DOI: 10.3390/cancers3043856.

29. Goldstein D., Laszlo J. The role of interferon in cancer therapy: a current perspective. CA Cancer J Clin 1988;38(5):258–77. DOI: 10.3322/canjclin.38.5.258.

30. Nicholas C., Lesinski G.B. Immunomodulatory cytokines as therapeutic agents for melanoma. Immunotherapy 2011;3(5):673–90. DOI: 10.2217/imt.11.45.

31. Ardolino M., Hsu J., Raulet D.H. Cytokine treatment in cancer immunotherapy. Oncotarget 2015;6(23):19346–7. DOI: 10.18632/oncotarget.5095.

32. Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4(1):11–22. DOI: 10.1038/nrc1252.

33. Dunn G.P., Koebel C.M., Schreiber R.D. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6(11):836–48. DOI: 10.1038/nri1961.

34. Coventry B.J., Ashdown M.L. The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses. Cancer Manag Res 2012;4(1):215–21. DOI: 10.2147/CMAR.S33979.

35. Constantinescu S.N., Croze E., Wang C. et al. Role of interferon alpha/beta receptor chain 1 in the structure and transmembrane signaling of the interferon alpha/beta receptor complex. Proceedings of the Nat Acad Sci 1994;91(20):9602–6. DOI: 10.1073/pnas.91.20.9602.

36. Katze M., He Y., Gale M. Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2002;2(1):675–87. DOI: 10.1038/nri888.

37. Müller L., Aigner P., Stoiber D. Type I interferons and natural killer cell regulation in cancer. Front Immunol 2017;8(304):1– 11. DOI: 10.3389/fimmu.2017.00304. eCollection 2017.

38. Trepiakas R., Pedersen A.E., Met Ö., Svane I.M. Addition of interferon-alpha to a standard maturation cocktail induces CD38 up-regulation and increases dendritic cell function. Vaccine 2009;27(16):2213–9. DOI: 10.1016/j.vaccine.2009.02.015.

39. Siegal F.P., Kadowaki N., Shodell M. et al. The nature of the principal type 1 interferon-producing cells in human blood. Science 1999;284(5421):1835–7. DOI: 10.1126/science.284.5421.1835.

40. Tarhini A.A., Cherian J., Moschos S.J. et al. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J Clin Oncol 2012;30(3):322–8. DOI: 10.1200/JCO.2011.37.5394.

41. Zeestraten E.C., Speetjens F.M., Welters M.J. et al. Addition of interferon α to the p53 SLP vaccine results in increased production of interferon γ in vaccinated colorectal cancer patients: a phase I/II clinical trial. Int J Cancer 2013;132(7):1581–91. DOI: 10.1002/ijc.27819.

42. Wang X., Rickert M., Garcia K.C. Structure of the quaternary complex of Interleukin-2 with Its α, β, and γ receptors. Science 2005;310(5751):1159–63. DOI: 10.1126/science.1117893.

43. Boyman O., Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol 2012;12(3):180–90. DOI: 10.1038/nri3156.

44. Waldmann T.A. Cytokines in cancer immunotherapy. Cold Spring Harb Perspect Biol 2018;10(12):a028472. DOI: 10.1101/cshperspect.a028472.

45. Lazer D., Pentland A.S., Adamic L. et al. Life in the network: the coming age of computational social science. Science 2009;323(5915):721–3. DOI: 10.1126/science.1167742.

46. Chen D.S., Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39(1):1–10. DOI: 10.1016/j.immuni.2013.07.012.

47. Ott P.A., Hodi F.S., Kaufman H.L. et al. Combination immunotherapy: a road map. J Immunother Cancer 2017;5(1):1–15. DOI: 10.1186/s40425-017-0218-5.

48. Krummel M.F., Allison J.P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995;182(2):459–65. DOI: 10.1084/jem.182.2.459.

49. Wilky B.A., Immune checkpoint inhibitors: the linchpins of modern immunotherapy. Immunol Rev 2019;290(1):6–23. DOI: 10.1111/imr.12766.

50. Schneider H., Smith X., Liu H. et al. CTLA-4 disrupts ZAP70 microcluster formation with reduced T cell/APC dwell times and calcium mobilization. Eur J Immunol 2008;38(1):40–7. DOI: 10.1002/eji.200737423.

51. Kubsch S., Graulich E., Knop J., Steinbrink K. Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol 2003;33(7):198897. DOI: 10.1002/eji.200323600.

52. Olsson C., Riebeck K., Dohlsten M., Michaëlsson E. CTLA-4 ligation suppresses CD28-induced NF-κB and AP-1 activity in mouse T cell blasts. J Biol Chem 1999;274(20):14400–5. DOI: 10.1074/jbc.274.20.14400.

53. Ishida Y., Agata Y., Shibahara K., Honjo T., Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11(11):3887–95. DOI: 10.1002/j.1460-2075.1992.tb05481.x.

54. Okazaki T., Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007;19(7):813–24. DOI: 10.1093/intimm/dxm057.

55. Riella L.V., Paterson A.M., Sharpe A.H., Chandraker A. Role of the PD-1 Pathway in the Immune Response. Am J Transplant 2012;12(10):2575–87. DOI: 10.1111/j.1600-6143.2012.04224.x.

56. Park J.J., Omiya R., Matsumura Y. et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 2010;116(8):1291–8. DOI: 10.1182/blood-2010-01-265975.

57. Topalian S.L., Hodi F.S., Brahmer J.R. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med 2012;366(26):2443–54. DOI: 10.1056/NEJMoa1200690.

58. Sharma P., Retz M., Siefker-Radtke A. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, singlearm, phase 2 trial. Lancet Oncol 2017;18(3):312–22. DOI: 10.1016/S14702045(17)30065-7.

59. Motzer R.J., Tannir N.M., McDermott D.F. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med2018;378(14):1277–90. DOI: 10.1056/NEJMoa1712126.

60. Patnaik A., Kang S.P., Rasco D. et al. Phase I study of pembrolizumab (MK3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res 2015;21(19):4286–93. DOI: 10.1158/1078-0432.CCR-14-2607.

61. Motzer R.J., Penkov K., Haanen J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380(12):1103–15. DOI: 10.1056/NEJMoa1816047.

62. Brahmer J.R., Tykodi S.S., Chow L.Q. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–65. DOI: 10.1056/NEJMoa1200694.

63. Powles T., O’Donnell P.H., Massard C. et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3(9):1–10. DOI: 10.1001/jamaoncol.2017.2411.

64. Schmid P., Cruz C., Braiteh F.S. et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. AACR 2017;77(13):1. DOI: 10.1158/1538-7445.AM2017-2986.

65. Postow M.A., Chesney J., Pavlick A.C. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372(21):2006–17. DOI: 10.1056/NEJMoa1414428.

66. Pfirschke C., Engblom C., Rickelt S., Cortez-Retamozo V. et al., Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 2016;44(2):343–54. DOI: 10.1016/j.immuni.2015.11.024.

67. Fyfe G., Fisher R.I., Rosenberg S.A. et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13(3):688–96. DOI: 10.1200/JCO.1995.13.3.688.

68. Rosenberg S.A., Yang J.C., White D.E., Steinberg S.M. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 1998;228(3):307–19. DOI: 10.1097/00000658-199809000-00004.

69. Merchant R.E., Grant A.J., Merchant L.H., Young H.F. Adoptive immunotherapy for recurrent glioblastoma multiforme using lymphokine activated killer cells and recombinant interleukin-2. Cancer 1988;62(4):665–71. DOI: 10.1002/1097-0142(19880815)62:4<665::AID-CNCR2820620403>3.0.CO;2-O.

70. Atkins M.B., Lotze M.T., Dutcher J.P. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17(7):2105. DOI: 10.1200/JCO.1999.17.7.2105.

71. Toh U., Yamana H., Sueyoshi S. et al. Locoregional cellular immunotherapy for patients with advanced esophageal cancer. Clin Cancer Res 2000;6(12):4663–73.

72. Nishiyama T., Tachibana M., Horiguchi Y. et al. Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24specific MAGE-3 peptide. Clin Cancer Res 2001;7(1):23–31.

73. Kabbinavar F., Hurwitz H.I., Fehrenbacher L. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21(1):60–5. DOI: 10.1200/JCO.2003.10.066.

74. Hurwitz H., Fehrenbacher L., Novotny W. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335–42. DOI: 10.1056/NEJMoa032691.

75. Davis I.D., Skrumsager B.K., Cebon J. et al. An open-label, two-arm, phase I trial of recombinant human interleukin-21 in patients with metastatic melanoma. Clin Cancer Res 2007;13(12):3630–6. DOI: 10.1158/1078-0432.CCR-07-0410.

76. Giantonio B.J., Catalano P.J., Meropol N.J. et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25(12):1539–44. DOI: 10.1200/JCO.2006.09.6305.

77. Iqbal S., Goldman B., Lenz H. et al. S0413: a phase II SWOG study of GW572016 (lapatinib) as first line therapy in patients (pts) with advanced or metastatic gastric cancer. J Clin Oncol 2007;25(18_suppl):4621. DOI: 10.1200/jco.2007.25.18_suppl.4621.

78. Hecht J.R., Mitchell E., Chidiac T. et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol 2009;27(5):672–80. DOI: 10.1200/JCO.2008.19.8135.

79. Petrella T.M., Tozer R., Belanger K. et al. Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol 2012;30(27):3396–401. DOI: 10.1200/JCO.2011.40.0655.

80. Gettinger S., Rizvi N.A., Chow L.Q. et al. Nivolumab monotherapy for first-line treatment of advanced non small-cell lung cancer. J Clin Oncol 2016;34(25):2980–7. DOI: 10.1200/JCO.2016.66.9929.

81. Eggermont A.M., Chiarion-Sileni V., Grob J.J. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375(19):1845–55. DOI: 10.1056/NEJMoa1611299.

82. Davar D., Ding F., Saul M. et al. Highdose interleukin-2 (HD IL-2) for advanced melanoma: a single center experience from the University of Pittsburgh Cancer Institute. J Immunother Cancer 2017;5(74):1–10. DOI: 10.1186/s40425017-0279-5.

83. Kok M., Horlings H., van de Vijver K. et al. LBA14Adaptive phase II randomized non-comparative trial of nivolumab after induction treatment in triple negative breast cancer: TONIC-trial. Ann Oncol 2017;28(suppl_5):1.

84. Hammers H.J., Plimack E.R., Infante J.R. et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol 2017;35(34):3851–8. DOI: 10.1200/JCO.2016.72.1985.

85. Абакушина Е.В., Пасова И.А., Почуев Т.П. и др. Адоптивная иммунотерапия активированными лимфоцитами в комплексной терапии пациентов с раком желудочно-кишечного тракта. Российский биотерапевтический журнал 2017;16(S1):3.

86. Escudier B., Motzer R.J., Sharma P. et al. Treatment beyond progression in patients with advanced renal cell carcinoma treated with nivolumab in CheckMate 025. Eur Urol 2017;72(3):368–76. DOI: 10.1016/j.eururo.2017.03.037.

87. Weber J., Mandala M., Del Vecchio M. et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;77(19):1824–35. DOI: 10.1056/NEJMoa1709030.

88. Adams S., Loi S., Toppmeyer D.L. et al. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triplenegative breast cancer (mTNBC). AACR 2018;78(4):1. DOI: 10.1158/1538-7445.SABCS17-PD6-10.

89. Buchbinder E.I., Dutcher J.P., Daniels G.A. et al. Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition. J Immunother Cancer 2019;7(1):1–7. DOI: 10.1186/s40425-019-0522-3.

90. Koster B.D., Santegoets S.J., Harting J. et al. Correction to: Autologous tumor cell vaccination combined with systemic CpG-B and IFN-α promotes immune activation and induces clinical responses in patients with metastatic renal cell carcinoma: a phase II trial. Cancer Immunol Immunotherap 2019;68(6):1037. DOI: 10.1007/s00262-019-02328-6.

91. Topalian S.L., Hodi F.S., Brahmer J.R. et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab. JAMA Oncol 2019;5(10):1411–20. DOI: 10.1001/jamaoncol.2019.2187.

92. Боробова Е.А., Жеравин А.А. Натуральные киллеры в иммунотерапии онкологических заболеваний. Сибирский онкологический журнал 2018;17(6):97–103. DOI: 10.21294/1814-48612018-17-6-97-104.

93. Davila M.L., Riviere I., Wang X. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Medi 2014;6(224):224–5. DOI: 10.1126/scitranslmed.3008226.

94. Xu Y., Zhang M., Ramos C.A. et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR. CD19-T cells and are preserved by IL-7 and IL-15. Blood 2014;123(24):3750–9. DOI: 10.1182/blood-2014-01-552174.