Advanced gastric cancers are responsible for overwhelming human suffering and death. Despite the development of combination chemotherapies, the survival rates of patients with gastric cancer remain unsatisfactory. Given the growing evidence of the benefits of immunotherapy as an alternative treatment for other cancers such as advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and refractory Hodgkin’s lymphoma, researchers have begun to explore its application in the treatment of gastric cancer. Three types of immunotherapy have shown promising effects against gastric cancer: immune checkpoint inhibitors, chimeric antigen rector (CAR)-T cells, and tumor vaccines. Clinical trials have used either immuno-oncology monotherapies or combination immuno-chemotherapies to improve the overall survival times and objective response rates of patients with gastric cancer. We review the clinical efficacy of immunotherapy including checkpoint inhibitors, CAR‑T, and tumor vaccines, in the treatment of gastric cancer. Based on initial evidence, we believe that immunotherapy could positively impact the natural history and improve the outcomes of a subgroup of patients with gastric cancer.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Ubukata H, Motohashi G, Tabuchi T, Nagata H, Konishi S, Tabuchi T. Evaluations of interferon-gamma/interleukin-4 ratio and neutrophil/lymphocyte ratio as prognostic indicators in gastric cancer patients. J Surg Oncol. 2010;102(7):742–7.
Chen LD, Flies B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227–42.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.
Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat. 2014;46(2):124–30.
Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6(1):74.
Han EQ, Li XL, Wang CR, Li TF, Han SY. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. J Hematol Oncol. 2013;6:47.
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480–9.
Masihi KN. Fighting infection using immunomodulatory agents. Expert Opin Biol Ther. 2001;1(4):641–53.
Banik D, Moufarrij S, Villagra A. Immunoepigenetics combination therapies: an overview of the role of HDACs in cancer immunotherapy. Int J Mol Sci. 2019;20(9):2241.
Koury J, Lucero M, Cato C, Chang L, Geiger J, Henry D, et al. Immunotherapies: exploiting the immune system for cancer treatment. J Immunol Res. 2018;2018:9585614.
Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651–68.
Naran K, Nundalall T, Chetty S, Barth S. Principles of immunotherapy: implications for treatment strategies in cancer and infectious diseases. Front Microbiol. 2018;9:3158.
Couzin-Frankel J. Breakthrough of the year 2013. Cancer Immunother Sci. 2013;342(6165):1432–3.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.
Scapin G, Yang X, Prosise WW, McCoy M, Reichert P, Johnston JM, et al. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat Struct Mol Biol. 2015;22(12):953–8.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.
Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–26.
Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123–33.
Study of pembrolizumab (MK-3475) as first‑line monotherapy and combination therapy for treatment of advanced gastric or gastroesophageal junction adenocarcinoma (MK-3475–062/KEYNOTE-062). www.https://clinicaltrials. gov/ct2/show/NCT02494583.
Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. 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):2461–71.
Boku N. A phase 3 study of nivolumab (Nivo) in previously treated advanced gastric or gastroesophageal junction (G/GEJ) cancer: updated results and subset analysis by pd-l1 expression (ATTRACTION-02). Ann Oncol. 2017;28:v209–68.
Ready NE, Ott PA, Hellmann MD, Zugazagoitia J, Hann CL, Braud F, et al. Nivolumab monotherapy and nivolmab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 ramdomized cohort. J Thocac Oncol. 2020;15(3):426–35.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.
Segal NHAS, Brahmer JR, Maio M, Blake-Haskins A, Vasselli XL, Ibrahim RA, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol. 2014;32:3002.
Keilholz U, Mehnert JM, Bauer S, Bourgeois H, Patel MR, Gravenor D, et al. Avelumab in patients with previously treated metastatic melanoma: phase 1b results from the JAVELIN solid tumor trial. J immunother Cancer. 2019. https://doi.org/10.1186/s40425-018-0459-y.
Markus H, Moehler MD, Ozguroglu M, Ryu M, Muntean AS, Lonardi S, et al. Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 2020;38:278.
Bang EYRY-J, Van Cutsem E, Lee K-W, Wyrwicz L, Schenker M, Alsina M, Phase III. randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018;29(10):2052–60.
Ipilimumab .https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm. Accessed 17 Sep 2020.
ClinicalTrials.gov: an efficacy study in gastric and gastroesophageal junction cancer comparing ipilimumab versus standard of care immediately following first line chemotherapy. https://clinicaltrials.gov/ct2/show/NCT01585987. Accessed 17 May 2016.
Ralph C, Elkord E, Burt DJ, O’Dwyer JF, Austin EB, Stern PL, Hawkins RE, Thistlethwaite FC. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010;16(5):1662–72.
Bang YJ, Cho JY, Kim YH, Kim JW, Di Bartolomeo M, Ajani JA, Yamaguchi K, Balogh A, Sanchez T, Moehler M. Efficacy of sequential ipilimumab monotherapy versus best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer. Clin Cancer Res. 2017;23(19):5671–8.
Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, Ott PA, Peltola K, Jaeger D, Evans J, De Braud F. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018;36(28):2836.
Mohme M, Riethdorf S, Pantel K. Circulating and disseminated tumour cells—mechanisms of immune surveillance and escape. Nat Rev Clin Oncol. 2017;14(3):155–67.
McNutt M. Cancer immunotherapy. Science. 2013;342(6165):1417.
Patel JM, Dale GA, Vartabedian VF, Dey P, Selvaraj P. Cancer CARtography: charting out a new approach to cancer immunotherapy. Immunotherapy. 2014;6(6):675–8.
Spear TT, Nagato K, Nishimura MI. Strategies to genetically engineer T cells for cancer immunotherapy. Cancer Immunol Immunother. 2016;65(6):631–49.
Zhang Q, Zhang Z, Peng M, Fu S, Xue Z, Zhang R. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside. Oncoimmunology. 2016;5(12):e1251539.
Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45–55.
Whilding LM, Maher J. ErbB-targeted CAR T-cell immunotherapy of cancer. Immunotherapy. 2015;7(3):229–41.
A clinical research of CAR-T cells targeting HER2 positive cancer. https://clinicaltrials.gov/ct2/show/NCT02713984. Accessed 19 Mar 2020.
ClinicalTrials.gov, Treatment of chemotherapy refractory human epidermalgrowth factor receptor-2(HER-2) positive advanced solid tumors (CART-HER-2). https://clinicaltrials.gov/ct2/show/NCT01935843. Accessed 28 Jan 2016.
Guest RD, Kirillova N, Mowbray S, Gornall H, Rothwell DG, Cheadle EJ, et al. Definition and application of good manufacturing process-compliant production of CEA-specific chimeric antigen receptor expressing T-cells for phase I/II clinical trial. Cancer Immunol Immunother. 2014;63(2):133–45.
ClinicalTrials.gov, CAR-T cell immunotherapy in MUC1 positive solid tumor. https://clinicaltrials.gov/ct2/show/NCT02617134. Accessed 6 Dec 2016.
ClinicalTrials.gov, Study evaluating the efficacy and safety with CAR-T for stomach cancer (EECSC). https://clinicaltrials.gov/ct2/show/NCT02725125. Accessed 23 Mar 2017.
Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217–21.
Ribas A, Butterfield LH, Glaspy JA, Economou JS. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol. 2003;21(12):2415–32.
Gilliam ADSA, Watson G. 17DT: an antigastrin immunogen for the treatment of gastrointestinal malignancy. Expert Opin Biol Ther. 2007;7(3):397–404.
Park DJ, Thomas NJ, Yoon C, Yoon SS. Vascular endothelial growth factor a inhibition in gastric cancer. Gastric Cancer. 2015;18(1):33–42.
Sundar R, Rha SY, Yamaue H, Katsuda M, Kono K, Kim HS, et al. A phase I/Ib study of OTSGC-A24 combined peptide vaccine in advanced gastric cancer. BMC Cancer. 2018;18(1):332.
Ajani JA, Hecht JR, Ho L, Baker J, Oortgiesen M, Eduljee A, et al. An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer: the GC4 study. Cancer. 2006;106(9):1908–16.
Wada S, Tsunoda T, Baba T, Primus FJ, Kuwano H, Shibuya M, et al. Rationale for antiangiogenic cancer therapy with vaccination using epitope peptides derived from human vascular endothelial growth factor receptor 2. Cancer Res. 2005;65(11):4939–46.
Ishizaki H, Tsunoda T, Wada S, Yamauchi M, Shibuya M, Tahara H. Inhibition of tumor growth with antiangiogenic cancer vaccine using epitope peptides derived from human vascular endothelial growth factor receptor 1. Clin Cancer Res. 2006;12(19):5841–9.
Masuzawa T, Fujiwara Y, Okada K, Nakamura A, Takiguchi S, Nakajima K, et al. Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. Int J Oncol. 2012;41(4):1297–304.
Ishikawa H, Imano M, Shiraishi O, Yasuda A, Peng YF, Shinkai M, et al. Phase I clinical trial of vaccination with LY6K-derived peptide in patients with advanced gastric cancer. Gastric Cancer. 2014;17(1):173–80.
ClinicalTrials.gov: Study of OTSGC-A24 vaccine in advanced gastric cancer. https://clinicaltrials.gov/ct2/show/NCT01227772. Accessed 22 June 2016.
Wang Q, Liu F, Liu L. Prognostic significance of PD-L1 in solid tumor: an updated meta-analysis. Medicine (Baltimore). 2017;96(18):e6369.
Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. 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):e180013.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. 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):31–9.
Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224–35.
Petty R, Anthoney A, Metges JP, Alsina M, Goncalves A, Brown J, et al. Phase Ib/II study of elisidepsin in metastatic or advanced gastroesophageal cancer (IMAGE trial). Cancer Chemother Pharmacol. 2016;77(4):819–27.
Bernstein MB, Krishnan S. Hodge JW Chang JY, Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016;13(8):516–24.
Tang C, Wang X, Soh H, Seyedin S, Cortez MA, Krishnan S, et al. Combining radiation and immunotherapy: a new systemic therapy for solid tumors? Cancer Immunol Res. 2014;2(9):831–8.
Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.
Lemke-Miltner CD, Blackwell SE, Yin C, Krug AE, Morris AJ, Krieg AM, et al. Antibody opsonization of a tlr9 agonist-containing virus-like particle enhances in situ immunization. J Immunol. 2020;204(5):1386–94.
Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8.
Khagi Y, Kurzrock R, Patel SP. Next generation predictive biomarkers for immune checkpoint inhibition. Cancer Metastasis Rev. 2017;36(1):179–90.
Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–58.
Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.
Solinas C, Pusole G, Demurtas L, Puzzoni M, Mascia R, Morgan G, et al. Tumor infiltrating lymphocytes in gastrointestinal tumors: controversies and future clinical implications. Crit Rev Oncol Hematol. 2017;110:106–16.
Ferris RL, Galon J. Additional Support for the Introduction of Immune Cell Quantification in Colorectal Cancer Classification. J Natl Cancer Inst. 2016;108(8):djw033.
Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the introduction of the “Immunoscore” in the classification of malignant tumours. J Pathol. 2014;232(2):199–209.
Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.
Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. primary resistance to pd-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7(2):188–201.
Conflict of interest
Akira Yoneda and his co-authors have no conflicts of interest to declare.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yoneda, A., Kuroki, T. & Eguchi, S. Immunotherapeutic advances in gastric cancer. Surg Today 51, 1727–1735 (2021). https://doi.org/10.1007/s00595-021-02236-2
- Gastric cancer