Frontiers of Medicine

, Volume 13, Issue 1, pp 12–23 | Cite as

Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects

  • Chenfei Zhou
  • Jun ZhangEmail author
Open Access


Strategies in comprehensive therapy for gastrointestinal (GI) cancer have been optimized in the last decades to improve patients’ outcomes. However, treatment options remain limited for late-stage or refractory diseases. The efficacy of immune checkpoint inhibitors (ICIs) for treatment of refractory GI cancer has been confirmed by randomized clinical trials. In 2017, pembrolizumab was approved by the US Food and Drug Administration as the first agent for treatment of metastatic solid tumors with mismatch repair deficiency, especially for colorectal cancer. Given the different mechanisms, oncologists have focused on determining whether ICIs-based combination strategies could achieve higher efficacy than conventional therapy alone in late-stage or even front-line treatment of GI cancer. This review discusses the current status of combining immune checkpoint inhibitors with molecular targeted therapy, chemotherapy, or radiotherapy in GI cancer in terms of mechanisms, safety, and efficacy to provide basis for future research.


gastrointestinal cancer immune checkpoint inhibitor combination therapy 



This study was supported by National Natural Science Foundation of China (No. 81802319).


  1. 1.
    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin 2016; 66(2): 115–132PubMedGoogle Scholar
  2. 2.
    Chen W, Zheng R, Zeng H, Zhang S, He J. Annual report on status of cancer in China, 2011. Chin J Cancer Res 2015; 27(1): 2–12PubMedPubMedCentralGoogle Scholar
  3. 3.
    Strong VE, Wu AW, Selby LV, Gonen M, Hsu M, Song KY, Park CH, Coit DG, Ji JF, Brennan MF. Differences in gastric cancer survival between the U.S. and China. J Surg Oncol 2015; 112(1): 31–37PubMedPubMedCentralGoogle Scholar
  4. 4.
    Yan S, Li B, Bai ZZ, Wu JQ, Xie DW, Ma YC, Ma XX, Zhao JH, Guo XJ. Clinical epidemiology of gastric cancer in Hehuang valley of China: a 10-year epidemiological study of gastric cancer.World J Gastroenterol 2014; 20(30): 10486–10494Google Scholar
  5. 5.
    Liao Y, Li S, Chen C, He X, Lin F, Wang J, Yang Z, Lan P. Screening for colorectal cancer in Tianhe, Guangzhou: results of combining fecal immunochemical tests and risk factors for selecting patients requiring colonoscopy. Gastroenterol Rep(Oxf) 2018; 6(2): 132–136Google Scholar
  6. 6.
    Lopez A, Harada K, Mizrak Kaya D, Ajani JA. Current therapeutic landscape for advanced gastroesophageal cancers. Ann Transl Med 2018; 6(4): 78PubMedPubMedCentralGoogle Scholar
  7. 7.
    Veenstra CM, Krauss JC. Emerging systemic therapies for colorectal cancer. Clin Colon Rectal Surg 2018; 31(3): 179–191PubMedGoogle Scholar
  8. 8.
    Jiménez-Sánchez A, Memon D, Pourpe S, Veeraraghavan H, Li Y, Vargas HA, Gill M B, Park KJ, Zivanovic O, Konner J, Ricca J, Zamarin D, Walther T, Aghajanian C, Wolchok JD, Sala E, Merghoub T, Snyder A, Miller ML. Heterogeneous tumor-immune microenvironments among differentially growing metastases in an ovarian cancer patient. Cell 2017; 170(5): 927–938.e920PubMedPubMedCentralGoogle Scholar
  9. 9.
    Lee K, Hwang H, Nam KT. Immune response and the tumor microenvironment: how they communicate to regulate gastric cancer. Gut Liver 2014; 8(2): 131–139PubMedPubMedCentralGoogle Scholar
  10. 10.
    Pérez-Ruiz E, Berraondo P. Immunological landscape and clinical management of rectal cancer. Front Immunol 2016; 7: 61PubMedPubMedCentralGoogle Scholar
  11. 11.
    Sanchez-Castañón M, Er TK, Bujanda L, Herreros-Villanueva M. Immunotherapy in colorectal cancer: what have we learned so far? Clin Chim Acta 2016; 460: 78–87PubMedGoogle Scholar
  12. 12.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357(6349): 409–413PubMedPubMedCentralGoogle Scholar
  13. 13.
    Anderson R, Rapoport BL. Immune dysregulation in cancer patients undergoing immune checkpoint inhibitor treatment and potential predictive strategies for future clinical practice. Front Oncol 2018; 8: 80PubMedPubMedCentralGoogle Scholar
  14. 14.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; the KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372(26): 2521–2532PubMedGoogle Scholar
  15. 15.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373(17): 1627–1639PubMedPubMedCentralGoogle Scholar
  16. 16.
    Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz S, Andre T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer(CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017; 18(9): 1182–1191PubMedPubMedCentralGoogle Scholar
  17. 17.
    Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol 2018; 4(5): e180013Google Scholar
  18. 18.
    Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, Chung HC, Chen JS, Muro K, Kang WK, Yeh KH, Yoshikawa T, Oh SC, Bai LY, Tamura T, Lee KW, Hamamoto Y, Kim JG, Chin K, Oh DY, Minashi K, Cho JY, Tsuda M, Chen LT. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens(ONO-4538–12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10111): 2461–2471PubMedGoogle Scholar
  19. 19.
    Kudo T, Hamamoto Y, Kato K, Ura T, Kojima T, Tsushima T, Hironaka S, Hara H, Satoh T, Iwasa S, Muro K, Yasui H, Minashi K, Yamaguchi K, Ohtsu A, Doki Y, Kitagawa Y. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017; 18(5): 631–639PubMedGoogle Scholar
  20. 20.
    Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, Mueller B, Quaratino S, Sabatos-Peyton C, Petruzzelli L, Engelman JA, Dranoff G. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 2017; 17(5): 286–301PubMedGoogle Scholar
  21. 21.
    Blair AB, Murphy A. Immunotherapy as a treatment for biliary tract cancers: a review of approaches with an eye to the future. Curr Probl Cancer 2018; 42(1): 49–58PubMedGoogle Scholar
  22. 22.
    Lee V, Murphy A, Le DT, Diaz LA Jr. Mismatch repair deficiency and response to immune checkpoint blockade. Oncologist 2016; 21(10): 1200–1211PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ciombor KK, Bekaii-Saab T. A comprehensive review of sequencing and combination strategies of targeted agents in metastatic colorectal cancer. Oncologist 2018; 23(1): 25–34PubMedGoogle Scholar
  24. 24.
    Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348(6230): 56–61PubMedGoogle Scholar
  25. 25.
    Chen DS, Mellman I. Oncology meets immunology: the cancerimmunity cycle. Immunity 2013; 39(1): 1–10PubMedGoogle Scholar
  26. 26.
    Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007; 121(1): 1–14PubMedPubMedCentralGoogle Scholar
  27. 27.
    Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin Cancer Res 2015; 21(4): 687–692PubMedGoogle Scholar
  28. 28.
    Muenst S, Laubli H, Soysal SD, Zippelius A, Tzankov A, Hoeller S. The immune system and cancer evasion strategies: therapeutic concepts. J Intern Med 2016; 279(6): 541–562PubMedGoogle Scholar
  29. 29.
    Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Senbabaoglu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano R A D, Eriksson P, Hoglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554(7693): 544–548PubMedPubMedCentralGoogle Scholar
  30. 30.
    Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, Sevillano M, Ibiza S, Canellas A, Hernando-Momblona X, Byrom D, Matarin JA, Calon A, Rivas EI, Nebreda AR, Riera A, Attolini CS, Batlle E. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018; 554(7693): 538–543PubMedGoogle Scholar
  31. 31.
    Ward-Hartstonge KA, Kemp RA. Regulatory T-cell heterogeneity and the cancer immune response. Clin Transl Immunology 2017; 6(9): e154Google Scholar
  32. 32.
    Sun J, Zhang Y, Yang M, Zhang Y, Xie Q, Li Z, Dong Z, Yang Y, Deng B, Feng A, Hu W, Mao H, Qu X. Hypoxia induces T-cell apoptosis by inhibiting chemokine C receptor 7 expression: the role of adenosine receptor A(2). Cell Mol Immunol 2010; 7(1): 77–82PubMedGoogle Scholar
  33. 33.
    Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 2009; 229(1): 12–26PubMedPubMedCentralGoogle Scholar
  34. 34.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252–264PubMedPubMedCentralGoogle Scholar
  35. 35.
    Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, Izzeddine H, Marabelle A, Champiat S, Berdelou A, Lanoy E, Texier M, Libenciuc C, Eggermont AM, Soria JC, Mateus C, Robert C. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016; 13(8): 473–486PubMedGoogle Scholar
  36. 36.
    Maj E, Papiernik D, Wietrzyk J. Antiangiogenic cancer treatment: the great discovery and greater complexity. Int J Oncol 2016; 49(5): 1773–1784PubMedPubMedCentralGoogle Scholar
  37. 37.
    Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS, Denker M, Leveque V, Canamero M, Babitski G, Koeppen H, Ziai J, Sharma N, Gaire F, Chen DS, Waterkamp D, Hegde PS, McDermott DF. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016; 7(1): 12624PubMedPubMedCentralGoogle Scholar
  38. 38.
    Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018; 15(5): 325–340PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ott PA, Hodi FS, Buchbinder EI. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: an overview of rationale, preclinical evidence, and initial clinical data. Front Oncol 2015; 5: 202PubMedPubMedCentralGoogle Scholar
  40. 40.
    Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L. Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 2005; 202(7): 919–929PubMedPubMedCentralGoogle Scholar
  41. 41.
    Terme M, Pernot S, Marcheteau E, Sandoval F, Benhamouda N, Colussi O, Dubreuil O, Carpentier AF, Tartour E, Taieb J. VEGFAVEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 2013; 73(2): 539–549PubMedGoogle Scholar
  42. 42.
    Gabrilovich D, Ishida T, Oyama T, Ran S, Kravtsov V, Nadaf S, Carbone DP. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998; 92(11): 4150–4166PubMedGoogle Scholar
  43. 43.
    Dikov MM, Ohm JE, Ray N, Tchekneva EE, Burlison J, Moghanaki D, Nadaf S, Carbone DP. Differential roles of vascular endothelial growth factor receptors 1 and 2 in dendritic cell differentiation. J Immunol 2005; 174(1): 215–222PubMedGoogle Scholar
  44. 44.
    Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, Hurwitz HI, Dev I, Nixon AB, Lyerly HK, Clay T, Morse MA. The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother 2008; 57(8): 1115–1124PubMedPubMedCentralGoogle Scholar
  45. 45.
    Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013; 73(10): 2943–2948PubMedPubMedCentralGoogle Scholar
  46. 46.
    Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res 2010; 70(15): 6171–6180PubMedPubMedCentralGoogle Scholar
  47. 47.
    Strickler JH, Hurwitz HI. Bevacizumab-based therapies in the firstline treatment of metastatic colorectal cancer. Oncologist 2012; 17(4): 513–524PubMedPubMedCentralGoogle Scholar
  48. 48.
    Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; the CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer(CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2015; 16(6): 619–629PubMedGoogle Scholar
  49. 49.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359(4): 378–390PubMedGoogle Scholar
  50. 50.
    Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol 2018; 15(10): 599–616PubMedGoogle Scholar
  51. 51.
    Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J; the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383(9911): 31–39PubMedGoogle Scholar
  52. 52.
    Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, Yagita H, Nakajima Y. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2(VEGFR2) induces synergistic anti-tumour effect in vivo. Clin Exp Immunol 2013; 172(3): 500–506PubMedPubMedCentralGoogle Scholar
  53. 53.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307(5706): 58–62PubMedGoogle Scholar
  54. 54.
    Hochster HS, Bendell JC, Cleary JM, Foster P, Zhang W, He X, Hernandez G, Iizuka K. 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(4_suppl): 673Google Scholar
  55. 55.
    Wallin J, Pishvaian MJ, Hernandez G, Yadav M, Jhunjhunwala S, Delamarre L, He X, Powderly J, Lieu C, Eckhardt SG, Hurwitz H, Hochster HS, Murphy J, Leveque V, Cha E, Funke R, Waterkamp D, Hegde P, Bendell J. Clinical activity and immune correlates from a phase Ib study evaluating atezolizumab(anti-PDL1) in combination with FOLFOX and bevacizumab(anti-VEGF) in metastatic colorectal carcinoma. Cancer Res, 2016, 76(14_suppl): 2651Google Scholar
  56. 56.
    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A,Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26(12): 2013–2019PubMedGoogle Scholar
  57. 57.
    Smyth E, Thuss-Patience PC. Immune checkpoint inhibition in gastro-oesophageal cancer. Oncol Res Treat 2018; 41(5): 272–280PubMedGoogle Scholar
  58. 58.
    Bang YJ, Golan T, Lin CC, Kang YK,Wainberg Z,Wasserstrom H, Jin J, Mi G, McNeely S, Laing N, Goff LW, Fu S. Interim safety and clinical activity in patients(pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction(G/ GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab(R) plus durvalumab(D). J Clin Oncol 2018; 36(4_suppl): 92Google Scholar
  59. 59.
    Ikeda M, Sung M W, Kudo M. A phase 1b trial of lenvatinib(LEN) plus pembrolizumab(PEM) in patients(pts) with unresectable hepatocellular carcinoma(uHCC). J Clin Oncol 2018; 36(suppl): abstr 4076Google Scholar
  60. 60.
    Stein S, Pishvaian M J, Lee M S. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma(HCC). J Clin Oncol 2018; 36(suppl): abstr 4074Google Scholar
  61. 61.
    Corraliza-Gorjón I, Somovilla-Crespo B, Santamaria S, Garcia-Sanz JA, Kremer L. New strategies using antibody combinations to increase cancer treatment effectiveness. Front Immunol 2017; 8: 1804PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ferris RL, Lenz HJ, Trotta AM, Garcia-Foncillas J, Schulten J, Audhuy F, Merlano M, Milano G. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. Cancer Treat Rev 2018; 63: 48–60PubMedGoogle Scholar
  63. 63.
    Inoue Y, Hazama S, Suzuki N, Tokumitsu Y, Kanekiyo S, Tomochika S, Tsunedomi R, Tokuhisa Y, Iida M, Sakamoto K, Takeda S, Ueno T, Yoshino S, Nagano H. Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer. Cancer Sci 2017; 108(3): 455–460PubMedPubMedCentralGoogle Scholar
  64. 64.
    Chen S, Li X, Chen R, Yin M, Zheng Q. Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model. Oncol Lett 2016; 12(3): 1868–1876PubMedPubMedCentralGoogle Scholar
  65. 65.
    Jie HB, Schuler PJ, Lee SC, Srivastava RM, Argiris A, Ferrone S, Whiteside TL, Ferris RL. CTLA-4(+) regulatory t cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res 2015; 75(11): 2200–2210PubMedPubMedCentralGoogle Scholar
  66. 66.
    Jie HB, Srivastava RM, Argiris A, Bauman JE, Kane LP, Ferris RL. Increased PD-1(+) and TIM-3(+) TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol Res 2017; 5(5): 408–416PubMedPubMedCentralGoogle Scholar
  67. 67.
    Inoue H, Horii R, Ito Y, Iwase T, Ohno S, Akiyama F. Tumorinfiltrating lymphocytes affect the efficacy of trastuzumab-based treatment in human epidermal growth factor receptor 2-positive breast cancer. Breast Cancer 2018; 25(3): 268–274PubMedGoogle Scholar
  68. 68.
    Chaganty BKR, Qiu S, Gest A, Lu Y, Ivan C, Calin GA, Weiner LM, Fan Z. Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion. Cancer Lett 2018; 430: 47–56PubMedGoogle Scholar
  69. 69.
    Catenacci D V, Park H, Uronis H E, Kang Y, Lacy J, Enzinger P C, Park S H, Lee K W. Margetuximab plus pembrolizumab in ERBB2-amplified PD-L1 + gastroesophageal adenocarcinoma post trastuzumab. J Clin Oncol 2018; 36(suppl): abstr 4030Google Scholar
  70. 70.
    Robert L, Ribas A, Hu-Lieskovan S. Combining targeted therapy with immunotherapy. Can 1 + 1 equal more than 2? Semin Immunol 2016; 28(1): 73–80PubMedPubMedCentralGoogle Scholar
  71. 71.
    Patel SA, Minn AJ. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 2018; 48(3): 417–433PubMedGoogle Scholar
  72. 72.
    Azad N S, Shirai K, McRee A J, Opyrchal M, Johnson D B, Ordentlich P, Brouwer S, Sankoh S, Schmidt E V, Meyers M L, Johnson M L. ENCORE 601: a phase 2 study of entinostat in combinationwith pembrolizumab in patients with microsatellite stable metastatic colorectal cancer. J Clin Oncol 2018; 36(suppl): abstr 3557Google Scholar
  73. 73.
    Bendell J, Kim TW, Goh B, Wallin J, Oh DY, Han SW, Lee C, Hellmann MD, Desai J, Lewin JH, Solomon B, Chow QM, Miller W, Gainor J, Flaherty K, Infante J, Das-Thakur M, Foster P, Cha E, Bang YJ. Clinical activity and safety of cobimetinib(cobi) and atezolizumab in colorectal cancer(CRC). J Clin Oncol 2016; 34(5_suppl): 3502Google Scholar
  74. 74.
    Bendell J, Ciardiello F, Tabernero J, Tebbutt N, Eng C, Bartolomeo M Di, Falcone A, Fakih M, Kozloff M, Segal N, Sobrero A, Shi Y, Roberts L, Yan Y, Chang I, Uyei A, Kim T. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab1cobimetinib and atezolizumab monotherapy vs. regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol 2018; 29(suppl_5): LBA-004Google Scholar
  75. 75.
    Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015; 161(2): 205–214PubMedPubMedCentralGoogle Scholar
  76. 76.
    Reits EA, Hodge JW, Herberts CA, Groothuis TA, Chakraborty M, Wansley EK, Camphausen K, Luiten RM, de Ru AH, Neijssen J, Griekspoor A, Mesman E, Verreck FA, Spits H, Schlom J, van Veelen P, Neefjes JJ. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006; 203(5): 1259–1271PubMedPubMedCentralGoogle Scholar
  77. 77.
    Young KH, Baird JR, Savage T, Cottam B, Friedman D, Bambina S, Messenheimer DJ, Fox B, Newell P, Bahjat KS, Gough MJ, Crittenden MR. Optimizing timing of immunotherapy improves control of tumors by hypofractionated radiation therapy. PLoS One 2016; 11(6): e0157164Google Scholar
  78. 78.
    Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer 2016; 2(6): 286–294PubMedPubMedCentralGoogle Scholar
  79. 79.
    Pico de Coaña Y, Choudhury A, Kiessling R. Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system. Trends Mol Med 2015; 21(8): 482–491Google Scholar
  80. 80.
    Xu X, Huang Z, Zheng L, Fan Y. The efficacy and safety of anti-PD-1/PD-L1 antibodies combined with chemotherapy or CTLA4 antibody as a first-line treatment for advanced lung cancer. Int J Cancer 2018; 142(11): 2344–2354PubMedGoogle Scholar
  81. 81.
    Blumenthal GM, Zhang L, Zhang H, Kazandjian D, Khozin S, Tang S, Goldberg K, Sridhara R, Keegan P, Pazdur R. Milestone analyses of immune checkpoint inhibitors, targeted therapy, and conventional therapy in metastatic non-small cell lung cancer trials: a metaanalysis. JAMA Oncol 2017; 3(8): e171029Google Scholar
  82. 82.
    Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC;the KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378(22): 2078–2092PubMedGoogle Scholar
  83. 83.
    Bang YJ, Muro K, Fuchs C, Golan T, Geva R, Hara H, Jalal SI, Borg C, Doi T, Wainberg Z, Wang JD, Koshiji M, Dalal R, Chung HC. KEYNOTE-059 cohort 2: safety and efficacy of pembrolizumab(pembro) plus 5-fluorouracil(5-FU) and cisplatin for first-line(1L) treatment of advanced gastric cancer. J Clin Oncol 2017; 35(15_suppl): 4012Google Scholar
  84. 84.
    Herrera FG, Bourhis J, Coukos G. Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 2017; 67(1): 65–85PubMedGoogle Scholar
  85. 85.
    Beg MS, Meyer J. Developing rational combinations of immune checkpoint inhibitors and radiation therapy for gastrointestinal cancers. J Gastrointest Oncol 2018; 9(1): 225–230PubMedPubMedCentralGoogle Scholar
  86. 86.
    Fiorica F, Belluomini L, Stefanelli A, Santini A, Urbini B, Giorgi C, Frassoldati A. Immune checkpoint inhibitor nivolumab and radiotherapy in pretreated lung cancer patients: efficacy and safety of combination. Am J Clin Oncol 2018 Jan 31. [Epub ahead of print] doi: 10.1097/COC.0000000000000428Google Scholar
  87. 87.
    Hilmi M, Bartholin L, Neuzillet C. Immune therapies in pancreatic ductal adenocarcinoma: where are we now? World J Gastroenterol 2018; 24(20): 2137–2151PubMedPubMedCentralGoogle Scholar
  88. 88.
    Bang YJ, Doi T, De Broud F, Piha-Paul S, Hollebecque A, Razak AR. Safety and efficacy of pembrolizumab(MK-3475) in patients(pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer 2015; 51(3): s112Google Scholar
  89. 89.
    Weinberg BA, Xiu J, Hwang JJ, Shields AF, Salem ME, Marshall JL. Immuno-oncology biomarkers for gastric and gastroesophageal junction adenocarcinoma: why PD-L1 testing may not be enough. Oncologist 2018; 23(10): 1171–1177PubMedGoogle Scholar
  90. 90.
    Deslypere G, Gullentops D, Wauters E, Vansteenkiste J. Immunotherapy in non-metastatic non-small cell lung cancer: can the benefits of stage IV therapy be translated into earlier stages? Ther Adv Med Oncol 2018; 10: 1758835918772810PubMedPubMedCentralGoogle Scholar
  91. 91.
    Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, Zahurak M, Yang SC, Jones DR, Broderick S, Battafarano RJ, Velez MJ, Rekhtman N, Olah Z, Naidoo J, Marrone KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom JW, Scharpf RB, White J, Gabrielson E, Wang H, Rosner GL, Rusch V, Wolchok JD, Merghoub T, Taube JM, Velculescu VE, Topalian SL, Brahmer JR, Pardoll DM. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018; 378(21): 1976–1986PubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2019

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, indicating if changes were made.

Authors and Affiliations

  1. 1.Department of OncologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina

Personalised recommendations