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Combinational Immunotherapy of Gastric Cancer

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Personalized Management of Gastric Cancer

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Abstract

Results from recent clinical trials using many novel immunotherapy strategies, including immune checkpoint blockade and adoptive T-cell therapy approaches (CAR T-cell and TCR T-cell therapy), have clearly demonstrated the importance of immunotherapy as a critical treatment strategy for gastric cancer patients. These therapies are additional options to the traditional treatment approaches of surgery, chemotherapy, radiotherapy, and targeted therapy. However, until now, immunotherapy has demonstrated clinical benefits in only a small fraction of patients. To improve the potential benefit of cancer immunotherapy, synergistic combinations of different immunotherapy approaches are currently being explored.

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References

  1. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016;13(5):273–90.

    Article  CAS  PubMed  Google Scholar 

  2. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001;345(10):725–30.

    Article  CAS  PubMed  Google Scholar 

  3. Niccolai E, Taddei A, Prisco D, Amedei A. Gastric cancer and the epoch of immunotherapy approaches. World J Gastroenterol. 2015;21(19):5778.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34.

    Article  PubMed  Google Scholar 

  5. Gilboa E. How tumors escape immune destruction and what we can do about it. Cancer Immunol Immunother. 1999;48(7):382–5.

    Article  CAS  PubMed  Google Scholar 

  6. Kershaw MH, Devaud C, John LB, Westwood JA, Darcy PK. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology. 2013;2(9):e25962.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lake RA, Robinson BW. Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer. 2005;5(5):397–405.

    Article  CAS  PubMed  Google Scholar 

  8. Kang TH, Mao C-P, Lee SY, Chen A, Lee J-H, Kim TW, et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 2013;73(8):2493–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    Article  CAS  PubMed  Google Scholar 

  10. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, et al. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol. 2010;22(3):113–24.

    Article  PubMed  Google Scholar 

  11. Vacchelli E, Senovilla L, Eggermont A, Fridman W, Galon J, Zitvogel L, et al. Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology. 2013;2:e23510.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kolstad A, Kumari S, Walczak M, Madsbu U, Hagtvedt T, Bogsrud TV, et al. Sequential intranodal immunotherapy induces antitumor immunity and correlated regression of disseminated follicular lymphoma. Blood. 2015;125(1):82–9.

    Article  CAS  PubMed  Google Scholar 

  13. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science. 2011;334(6062):1573–7.

    Article  CAS  PubMed  Google Scholar 

  14. Arlen PM, Gulley JL, Parker C, Skarupa L, Pazdur M, Panicali D, et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate cancer. Clin Cancer Res. 2006;12(4):1260–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–9.

    Article  CAS  PubMed  Google Scholar 

  16. Sharabi A, Haran-Ghera N. Immune recovery after cyclophosphamide treatment in multiple myeloma: implication for maintenance immunotherapy. Bone Marrow Res. 2011;2011:269519.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Heylmann D, Bauer M, Becker H, Van Gool S, Bacher N, Steinbrink K, et al. Human CD4+ CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS One. 2013;8(12):e83384.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013;38(4):729–41.

    Article  CAS  PubMed  Google Scholar 

  19. Ko H-J, Kim Y-J, Kim Y-S, Chang W-S, Ko S-Y, Chang S-Y, et al. A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res. 2007;67(15):7477–86.

    Article  CAS  PubMed  Google Scholar 

  20. Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 2003;63(15):4490–6.

    CAS  PubMed  Google Scholar 

  21. Zheng Y, Dou Y, Duan L, Cong C, Gao A, Lai Q, et al. Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer. Cell Immunol. 2015;294(1):54–9.

    Article  CAS  PubMed  Google Scholar 

  22. Hsu F-T, Chen T-C, Chuang H-Y, Chang Y-F, Hwang J-J. Enhancement of adoptive T cell transfer with single low dose pretreatment of doxorubicin or paclitaxel in mice. Oncotarget. 2015;6(42):44134–50.

    PubMed  PubMed Central  Google Scholar 

  23. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29(4):482–91.

    Article  CAS  PubMed  Google Scholar 

  24. Gonzalez-Aparicio M, Alzuguren P, Mauleon I, Medina-Echeverz J, Hervas-Stubbs S, Mancheno U, et al. Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice. Gut. 2011;60(3):341–9.

    Article  CAS  PubMed  Google Scholar 

  25. Correale P, Cusi MG, Tsang KY, Del Vecchio MT, Marsili S, La Placa M, et al. Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients. J Clin Oncol. 2005;23(35):8950–8.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    CAS  PubMed  Google Scholar 

  27. Noguchi M, Moriya F, Koga N, Matsueda S, Sasada T, Yamada A, et al. A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer. Cancer Immunol Immunother. 2016;65:151–60.

    Article  CAS  PubMed  Google Scholar 

  28. Cui J, Li L, Wang C, Jin H, Yao C, Wang Y, et al. Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma. Cytotherapy. 2015;17(7):979–88.

    Article  CAS  PubMed  Google Scholar 

  29. Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013;123(7):2756–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cui J, Wang N, Zhao H, Jin H, Wang G, Niu C, et al. Combination of radiofrequency ablation and sequential cellular immunotherapy improves progression-free survival for patients with hepatocellular carcinoma. Int J Cancer. 2014;134(2):342–51.

    Article  PubMed  Google Scholar 

  31. Mole R. Whole body irradiation—radiobiology or medicine? Br J Radiol. 1953;26(305):234–41.

    Article  CAS  PubMed  Google Scholar 

  32. Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114(3):589–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu LL, Smith MJ, Sun BS, Wang GJ, Redmond HP, Wang JH. Combined IFN-γ-endostatin gene therapy and radiotherapy attenuates primary breast tumor growth and lung metastases via enhanced CTL and NK cell activation and attenuated tumor angiogenesis in a murine model. Ann Surg Oncol. 2009;16(5):1403–11.

    Article  PubMed  Google Scholar 

  35. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  Google Scholar 

  36. Matsumura S, Wang B, Kawashima N, Braunstein S, Badura M, Cameron TO, et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol. 2008;181(5):3099–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ganss R, Ryschich E, Klar E, Arnold B, Hämmerling GJ. Combination of T-cell therapy and trigger of inflammation induces remodeling of the vasculature and tumor eradication. Cancer Res. 2002;62(5):1462–70.

    CAS  PubMed  Google Scholar 

  38. Kleponis J, Skelton R, Zheng L. Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors. Cancer Biol Med. 2015;12(3):201.

    PubMed  PubMed Central  Google Scholar 

  39. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lipson EJ, Sharfman WH, Drake CG, Wollner I, Taube JM, Anders RA, 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.

    Article  CAS  PubMed  Google Scholar 

  41. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014;2(7):616–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zheng L. Does vaccine-primed pancreatic cancer offer better candidates for immune-based therapies? Immunotherapy. 2014;6(10):1017–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Karyampudi L, Lamichhane P, Scheid AD, Kalli KR, Shreeder B, Krempski JW, et al. Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer Res. 2014;74(11):2974–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors. J Immunother. 2015;38(1):1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36(7):382–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wada S, Jackson CM, Yoshimura K, Yen H-R, Getnet D, Harris TJ, et al. Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. J Transl Med. 2013;11(1):1–89.

    Article  Google Scholar 

  48. John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013;19(20):5636–46.

    Article  CAS  PubMed  Google Scholar 

  49. Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 2012;72(20):5209–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;2015(373):23–34.

    Article  Google Scholar 

  51. Linch SN, McNamara MJ, Redmond WL. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front Oncol. 2015;5:34.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Redmond WL, Linch SN, Kasiewicz MJ. Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. Cancer Immunol Res. 2014;2(2):142–53.

    Article  CAS  PubMed  Google Scholar 

  53. Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013;123(6):2447–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One. 2014;9(2):e89350.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19(5):997–1008.

    Article  CAS  PubMed  Google Scholar 

  56. Atkins MB, Larkin J. Immunotherapy combined or sequenced with targeted therapy in the treatment of solid tumors: current perspectives. J Natl Cancer Inst. 2016;108(6):djv414.

    Article  PubMed  Google Scholar 

  57. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.

    Article  CAS  PubMed  Google Scholar 

  58. Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. ASCO Annual Meeting Proceedings; 2015.

    Google Scholar 

  59. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci. 2012;109(43):17561–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Garber K. Promising early results for immunotherapy-antiangiogenesis combination. J Natl Cancer Inst. 2014;106(11):dju392.

    Article  PubMed  Google Scholar 

  61. Terme M, Colussi O, Marcheteau E, Tanchot C, Tartour E, Taieb J. Modulation of immunity by antiangiogenic molecules in cancer. Clin Dev Immunol. 2012;2012:492920.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. 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):500–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hodi FS, Lawrence D, Lezcano C, Wu X, Zhou J, Sasada T, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res. 2014;2(7):632–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China

    Juan Du & Baorui Liu

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  1. The Comprehensive Cancer Center Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Jia Wei

  2. The Comprehensive Cancer Center Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

    Baorui Liu

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Du, J., Liu, B. (2017). Combinational Immunotherapy of Gastric Cancer. In: Wei, J., Liu, B. (eds) Personalized Management of Gastric Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-10-3978-2_12

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