Некоторые аспекты иммунотерапии при раке толстой кишки

Рак толстой кишки является примером опухоли, резистентной к иммунотерапевтическим подходам, тем не менее за последние несколько лет удалось выделить подгруппу пациентов, отвечающих на применение анти-PD-1-моноклональных антител. Это побудило молекулярных биологов, иммунологов и клинических онкологов вновь вернуться к теме иммунотерапии при данной патологии. К настоящему времени накопилось достаточное число работ, посвященных этой теме, что позволило нам подготовить обзор литературы, целью которого явилось обозначить основные направления иммунологии при раке толстой кишки: оценку прогностической значимости опухоль-инфильтрирующих лимфоцитов, эффективность применения ингибиторов иммунных чек-поинтов, биспецифических моноклональных антител и противоопухолевых вакцин, пути перевода невоспалительного фенотипа опухоли в воспалительный.

1. Galon J., Costes A., Sanchez-Cabo F. et al. Type, density and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–4. PMID: 17008531. DOI: 10.1126/science.1129139.

2. Mlecnik B., Tosolini M., Kirilovsky A. et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol 2011;29(6):610–8. PMID: 21245428. DOI: 10.1200/JCO.2010.30.5425.

3. Pagys F., Kirilovsky A., Mlecnik B. et al. In situ cytotoxic and memory T-cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009;27(35):5944–51. PMID: 19858404. DOI: 10.1200/JCO.2008.19.6147.

4. Salama P., Phillips M., Grieu F. et al. Tumor-infiltrating FOXP3+ T-regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 2009;27(2):186–92. PMID: 19064967. DOI: 10.1200/JCO.2008.18.7229.

5. Correale P., Rotundo M. S., Del Vecchio M. T. et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother 2010;33(4):435–41. PMID: 20386463. DOI: 10.1097/CJI. 0b013e3181d32f01.

6. Frey D. M., Droeser R. A., Viehl C. T. et al. High frequency of tumor-infiltrating FOXP3(+) regulatory T cells predicts improved survival in mismatch repair-proficient colorectal cancer patients. Int J Cancer 2010;126(11):2635–43. PMID: 19856313. DOI: 10.1002/ijc.24989.

7. Nosho K., Baba Y., Tanaka N. et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010;222(4):350–66. PMID: 20927778. DOI: 10.1002/path.2774.

8. Sinicrope F. A., Rego R. L., Ansell S. M. et al. Intraepithelial effector(CD3+)/regulatory(FoxP3+) T-cell ratio predicts a clinical outcome of human colon carcinoma. Gastroenterology 2009;137(4):1270–9. PMID: 19577568. DOI: 10.1053/j.gastro.2009.06.053.

9. Ladoire S., Martin F., Ghiringhelli F. Prognostic role of FOXP3+ regulatory T-cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 2011;60(7):909–18. PMID: 21644034. DOI: 10.1007/s00262-011-1046-y.

10. Camus M., Tosolini M., Mlecnik B. et al. Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 2009;69(6):2685–93. PMID: 19258510. DOI: 10.1158/0008-5472.CAN-08-2654.

11. Boland C. R., Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073–87. PMID: 20420947. DOI: 10.1053/j.gastro.2009.12.064.

12. Kim H., Jen J., Vogelstein B., Hamilton S. R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994;145(1):148–56. PMID: 8030745. PMCID: PMC1887287.

13. Dolcetti R., Viel A., Doglioni C. et al. High prevalence of activated intra-epithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with micro-satellite instability. Am J Pathol 1999; 154(6):1805–13. PMID: 10362805. DOI: 10.1016/S0002-9440(10) 65436-3.

14. Smyrk T. C., Watson P., Kaul K., Lynch H. T. Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 2001;91(12):2417–22.

15. Giannakis M., Mu X. J., Shukla S. A. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep 2016;15(4):857–65. PMID: 2714984. DOI: 10.1016/j.celrep.2016.03.075.

16. Gryfe R., Kim H., Hsieh E. T. et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med 2000;342(2):69–77. PMID: 10631274. DOI: 10.1056/NEJM200001133420201.

17. Guidoboni M., Gafа R., Viel A. et al. Microsatellite instability and high content of activated cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol 2001;159(1): 297–304. PMID: 11438476. DOI: 10.1016/S0002-9440(10)61695-1.

18. Michel S., Benner A., Tariverdian M. et al. High density of FOXP3-positive T-cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer 2008;99(11):1867–73. PMID: 18985040. DOI: 10.1038/sj.bjc.6604756.

19. De la Chapelle A., Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 2010;28(20):3380–7. PMID: 20516444. DOI: 10.1200/JCO.2009.27.0652.

20. Piton N., Borrini F., Bolognese A. et al. KRAS and BRAF mutation detection: is immunohistochemistry a possible alternative to molecular biology in colorectal cancer? Gastroenterol Res Pract 2015;2015:753903. PMID: 25983749. DOI: 10.1155/2015/753903.

21. Dienstmann R., Vermeulen L., Guinney J. et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 2017;17(2):79–92. DOI: 10.1038/nrc.2016.126.

22. Zinselmeyer B. H., Heydari S., Sacristan C. et al. PD-1 promotes immune exhaustion by inducing antiviral T-cell motility paralysis. J Exp Med 2013;210(4):757–74. DOI: 10.1084/jem.20121416.

23. De Guillebon E., Roussille P., Frouin E., Tougeron D. Anti program death-1/anti program deathligand 1 in digestive cancers. World J Gastrointest Oncol 2015;7(8):95–101. DOI: 10.4251/wjgo.v7.i8.95.

24. Llosa N. J., Cruise M., Tam A. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5(1):43–51. PMID: 25358689. DOI: 10.1158/2159-8290.CD-14-0863.

25. Fusi A., Festino L., Botti G. et al. PD-L1 expression as a potential predictive biomarker. Lancet Oncol 2015;16(13):1285–7. DOI: 10.1016/S1470-2045(15)00307-1.

26. Wu X., Zhang H., Xing Q. et al. PD-1(+) CD8(+) T-cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients. Br J Cancer 2014;111(7):1391–9. DOI: 10.1038/bjc.2014.416.

27. Gatalica Z., Snyder C. L., Yeatts K. et al. Programmed death 1(PD-1) lymphocytes and ligand (PD-L1) in colorectal cancer and their relationship to microsatellite instability status. J Clin Oncol 2014;32(Suppl 15):3625.

28. Droeser R. A., Hirt C., Viehl C. T. et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer 2013;49(9):2233–42. DOI: 10.1016/j.ejca.2013.02.015.

29. Fusi A., Festino L., Botti G. et al. PD-L1 expression as a potential predictive biomarker. Lancet Oncol 2015;16(13):1285–7. DOI: 10.1016/S1470-2045(15)00307-1.

30. Iwai Y., Terawaki S., Honjo T. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T-cells. Int Immunol 2005;17(2):133–44. PMID: 15611321. DOI: 10.1093/intimm/dxh194.

31. Duraiswamy J., Kaluza K. M., Freeman G. J., Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 2013;73(12):3591–603. PMID: 23633484. DOI: 10.1158/0008-5472.CAN-12-4100.

32. Topalian S. L., Hodi F. S., Brahmer J. R. et al. Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443–54. PMID: 22658127. DOI: 10.1056/NEJMoa1200690.

33. Brahmer J. R., Tykodi S. S., Chow L. Q. M. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–65. PMID: 22658128. DOI: 10.1056/NEJMoa1200694.

34. Herbst R. S., Soria J.-C., Kowanetz M. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515(7528):563–7. PMID: 25428504. DOI:10.1038/nature14011.

35. Lipson E. J., Sharfman W. H., Drake C. G. et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 2013;19(2):462–8. PMID: 23169436. DOI: 10.1158/1078-0432.CCR-12-2625.

36. Федянин М. Ю., Трякин А. А., Тюляндин С. А. Роль микросателлитной нестабильности при раке толстой кишки. Онкологическая колопроктология 2012;(3):19–25. [Fedyanin M. Yu., Tryakin A. A., Tyulyandin S. A. The role of microsatellite instability in colon cancer. Onkologicheskaya koloproktologiya = Colorectal Oncology 2012;(3):19–25. (In Russ.)].

37. Le D. T., Uram J. N., Wang H. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372(26):2509–20. PMID: 26028255. DOI: 10.1056/NEJMoa1500596.

38. Study of pembrolizumab (MK-3475) as monotherapy in participants with previously-treated locally advanced unresectable or metastatic colorectal cancer (MK-3475-164/KEYNOTE-164). Available at: http://clinicaltrials.gov/ show/ NCT02460198.

39. Study of pembrolizumab (MK-3475) vs. standard therapy in participants with microsatellite instability-high(MSI-H) or mismatch repair deficient(dMMR) sage IV colorectal carcinoma (MK-3475-177/ KEYNOTE-177). Available at: http:// clinicaltrials.gov/show/ NCT02563002.

40. Evaluate the efficacy of MEDI4736 in immunological subsets of advanced colorectal cancer. Available at: http:// clinicaltrials.gov/show/ NCT02227667.

41. Larkin J., Hodi F. S., Wolchok J. D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373(13):23–34. PMID: 26398076. DOI: 10.1056/NEJMc1509660.

42. Overman S. K., McDermott R.S., Leach J. et al. A study of nivolumab and nivolumab plus ipilimumab in recurrent and metastatic colon cancer (CheckMate 142). J Clin Oncol 2016;34(Suppl): 3501.

43. Andre T., Lonardi S., Wong M. et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J Clin Oncol 2018;36(Suppl 4S):553.

44. Overman M. J., Bergamo F., McDermott R. S. et al. Nivolumab in patients with DNA mismatch repair-deficient/ microsatellite instability-high (dMMR/ MSI-H) metastatic colorectal cancer (mCRC): long-term survival according to prior line of treatment from CheckMate-142. J Clin Oncol 2018:36(Suppl 4S): 554.

45. Woo S.-R., Turnis M. E., Goldberg M. V. et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012;72(4):917–27. PMID: 22186141. DOI: 10.1158/0008-5472.CAN-11-1620.

46. An investigational immunotherapy study of nivolumab and nivolumab in combination with other anti-cancer drugs in colon cancer that has come back or has spread. Available at: http://clinicaltrials. gov/show/ NCT02563002.

47. Soares K. C., Rucki A. A., Wu A. A. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother 2015;(3891):1–11. PMID: 25415283. DOI: 10.1097/CJI.0000000000000062.

48. Phase 2 study of GVAX (with CY) and pembrolizumab in MMR-p advanced colorectal cancer. Available at: http:// clinicaltrials.gov/show/NCT02981524.

49. Voron T., Colussi O., Marcheteau E. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T-cells in tumors. J Exp Med 2015;212(2): 139–48. PMID: 25601652. DOI: 10.1084/jem.20140559

50. Hochster H. S., Bendell J. C., Cleary J. M. et al. Efficacy and safety of atezolizumab (atezo) and bevacizumab (bev) in a phase Ib study of microsatellite instability (MSI) – high metastatic colorectal cancer (mCRC). J Clin Oncol 2017; 35(Suppl 4S): 673.

51. Nowak A. K., Lake R. A., Marzo A. L. et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T-cells. J Immunol 2003;170(10): 4905–13. PMID: 12734333

52. Mundy-Bosse B. L., Lesinski G. B., Jaime-Ramirez A. C. et al. Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Res 2011;71(15):5101–10. PMID: 21680779. DOI: 10.1158/ 0008–5472.CAN-10-2670.

53. Vincent J., Mignot G., Chalmin F. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T-cell-dependent antitumor immunity. Cancer Res 2010;70(8):3052–61. PMID: 20388795. DOI: 10.1158/ 0008-5472.CAN-09-3690.

54. Lesterhuis W. J., Punt C. J., Hato S. V. et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 2011;121(8):3100–8. PMID: 21765211. PMCID: PMC3148725 DOI: 10.1172/JCI43656.

55. Bendell J. C., Powderly J. D., Lieu C. H. et al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC). ASCO Meet Abst 2015;(33):704.

56. Goldberg R. M., Sargent D. J., Morton R. F. et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22(1):23–30. PMID: 14665611. DOI: 10.1200/JCO.2004.09.046.

57. Ebert P. J., Cheung J., Yang Y. et al. MAP kinase inhibition promotes T-сell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 2016;44(3):609–21. PMID: 26944201. DOI: 10.1016/j.immuni.2016.01.024.

58. Bendell J. C., Kim T. W., Goh B. C. et al. Clinical activity and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC). J Clin Oncol 2016; 34(Suppl):3502.

59. A study to investigate efficacy and safety of cobimetinib plus atezolizumab and atezolizumab monotherapy versus regorafenib in participants with metastatic colorectal adenocarcinoma (COTEZO IMblaze370). Available at: http:// clinicaltrials.gov/show/ NCT02788279.

60. Study of binimetinib + nivolumab plus or minus ipilimumab in patients with previously treated microsatellite-stable (MSS) metastatic colorectal cancer with RAS mutation. Available at: http:// clinicaltrials.gov/show/ NCT03271047.

61. Postow M. A., Callahan M. K., Barker C. A. et al. Immunologic correlates of the abs-copal effect in a patient with melanoma. N Engl J Med 2012;366(10):925–31. PMID: 22397654. DOI: 10.1056/NEJMoa1112824.

62. Segal N. H., Kemeny N. E., Cercek A. et al. Non-randomized phase II study to assess the efficacy of pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) patients. J Clin Oncol 2016;34(Suppl): 3539.

63. Study to nivolumab following preoperative chemoradiotherapy. Available at: http:// clinicaltrials.gov/show/ NCT02948348.

64. Tabernero J., Melero I., Ros W. et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2017;35(Suppl): 3002.

65. Correale P., Botta C., Ciliberto D. et al. Immunotherapy of colorectal cancer: new perspectives after a long path. Immunotherapy 2016;8(11):1281–92. PMID: 27993089. DOI: 10.2217/imt-2016-0089.

66. Harris J. E., Ryan L., Hoover H. C.Jr. et al. Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin. Oncol 2000;18(1):148–57. PMID: 10623705. DOI: 10.1200/JCO.2000.18.1.148.

67. Hanna M. G. Jr., Hoover H. C. Jr., Vermorken J. B. et al. Adjuvant active specific immunotherapy of stage II and stage III colon cancer with an autologous tumor cell vaccine: first randomized phase III trials show promise. Vaccine 2001;19(17–19):2576–82. PMID: 11257395.

68. Rao B., Han M., Wang L. et al. Clinical outcomes of active specific immuno-therapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review. J Transl Med 2011;9:17. PMID: 21272332. DOI: 10.1186/1479-5876-9-17.

69. Pol J., Kroemer G., Galluzzi L. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology 2015;5(1):e1115641. PMID: 26942095. OI: 10.1080/2162402X.2015.1115641.

70. Ockert D., Schirrmacher V., Beck N. et al. Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 1996;2(1):21–8. PMID: 9816085.

71. Kaufman H. L., Lenz H. J., Marshall J. et al. Combination chemotherapy and ALVAC-CEA/B7.1 vaccine in patients with metastatic colorectal cancer. Clin Cancer Res 2008;14(15):4843–9. PMID: 18676757. DOI: 10.1158/1078-0432.CCR-08-0276.

72. Reolysin in combination with FOLFOX6 and bevacizumab or FOLFOX6 and bevacizumab alone in metastatic colorectal cancer. Available at: http:// clinicaltrials.gov/show/NCT01622543.

73. Study of REOLYSIN® in combination with FOLFIRI and bevacizumab in FOLFIRI naive patients with KRAS mutant metastatic colorectal cancer. Available at: http://clinicaltrials.gov/ show/ NCT01274624.

74. Moingeon P. Recombinant cancer vaccines based on viral vectors. Dev Biol (Basel) 2004;116:117–22. PMID: 15603188.

75. Marshall J. Carcinoembryonic antigen-based vaccines. Semin Oncol 2003;30(3 Suppl 8):30–6. PMID: 12881810.

76. Correale P., Botta C., Ciliberto D. et al. Immunotherapy of colorectal cancer: new perspectives after a long path. Immunotherapy 2016;8(11):1281–92. PMID: 27993089. DOI: 10.2217/imt-2016-0089.

77. Xiang B., Snook A. E., Magee M. S., Waldman S. A. Colorectal cancer immunotherapy. Disc Med 2013;15(84):301–8. PMID: 23725603.