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Immunotherapy for GI Malignancies, Ready for Prime Time?

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Gastrointestinal (GI) cancers include esophageal, gastric, pancreatic, hepatobiliary, and colorectal malignancies. Immunotherapy has proved to be an important treatment method for cancer, and its use for a wide range of GI malignancies has been evaluated recently. This article discusses the type and mechanism of various immunotherapies under investigation in GI cancer. The study also reviews recent clinical trials, with a particular focus on overall survival, and discusses their achievements and limitations. Immunotherapy has shown efficacy for microsatellite instability high colorectal cancer and some promise in some gastroesophageal junction and gastric cancers. Meanwhile, it has not been effective for pancreatic or neuroendocrine tumors. The identification of novel biomarkers likely will guide selection of therapy for individual patients. Nevertheless, immunotherapy for GI cancers is in its infancy, and many other classes of immune therapies are being developed besides anti-PD1 and anti-PDL1. Thus, although immunotherapy has not seen a dramatic advance to date, it still has great potential.

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References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    Article  Google Scholar 

  2. Leko V, Rosenberg SA. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell. 2020;38:454–72.

    Article  CAS  Google Scholar 

  3. Maleki Vareki S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J Immunother Cancer. 2018;6:157.

    Article  Google Scholar 

  4. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:909–15.

    Article  CAS  Google Scholar 

  5. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184:5309–37.

    Article  CAS  Google Scholar 

  6. Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell. 2018;33(843–52):e4.

    Google Scholar 

  7. Parkhurst MR, Robbins PF, Tran E, Prickett TD, Gartner JJ, Jia L, et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov. 2019;9:1022–35.

    Article  CAS  Google Scholar 

  8. Lei M, Siemers NO, Pandya D, Chang H, Sanchez T, Harbison C, et al. Analyses of PD-L1 and inflammatory gene expression association with efficacy of nivolumab ± ipilimumab in gastric cancer/gastroesophageal junction cancer. Clin Cancer Res. 2021;27:3926–35.

    Article  CAS  Google Scholar 

  9. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384:1191–203.

    Article  CAS  Google Scholar 

  10. Wang W, Wu L, Zhang J, Wu H, Han E, Guo Q. Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model. Biochem Biophys Res Commun. 2017;487:1–7.

    Article  CAS  Google Scholar 

  11. Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, et al. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:234–47.

    Article  CAS  Google Scholar 

  12. Moehler M, Dvorkin M, Boku N, Ozguroglu M, Ryu MH, Muntean AS, et al. Phase III trial of avelumab maintenance after first-line induction chemotherapy versus continuation of chemotherapy in patients with gastric cancers: results from JAVELIN Gastric 100. J Clin Oncol. 2021;39:966–77.

    Article  CAS  Google Scholar 

  13. Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6:1571–80.

    Article  Google Scholar 

  14. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40.

    Article  CAS  Google Scholar 

  15. Kato K, Shah MA, Enzinger P, Bennouna J, Shen L, Adenis A, et al. KEYNOTE-590: phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol. 2019;15:1057–66.

    Article  CAS  Google Scholar 

  16. Janjigian YY, Kawazoe A, Yanez P, Li N, Lonardi S, Kolesnik O, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600:727–30.

    Article  CAS  Google Scholar 

  17. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383:2207–18.

    Article  CAS  Google Scholar 

  18. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. New Engl J Med. 2022. https://doi.org/10.1200/JCO.2022.40.4_suppl.016.

    Article  Google Scholar 

  19. Eng C, Kim TW, Bendell J, Argiles G, Tebbutt NC, Di Bartolomeo M, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (Imblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20:849–61.

    Article  CAS  Google Scholar 

  20. Huh JW, Lee JH, Kim HR. Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Arch Surg. 2012;147:366–72.

    Article  Google Scholar 

  21. Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391:2128–39.

    Article  Google Scholar 

  22. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.

    Article  CAS  Google Scholar 

  23. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38:1–10.

    Article  CAS  Google Scholar 

  24. Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15:829–40.

    Article  CAS  Google Scholar 

  25. Le DT, Picozzi VJ, Ko AH, Wainberg ZA, Kindler H, Wang-Gillam A, et al. Results from a phase IIb, randomized, multicenter study of GVAX pancreas and CRS-207 compared with chemotherapy in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE study). Clin Cancer Res. 2019;25:5493–502.

    Article  CAS  Google Scholar 

  26. Tsujikawa T, Crocenzi T, Durham JN, Sugar EA, Wu AA, Onners B, et al. Evaluation of cyclophosphamide/GVAX pancreas followed by listeria-mesothelin (CRS-207) with or without nivolumab in patients with pancreatic cancer. Clin Cancer Res. 2020;26:3578–88.

    Article  CAS  Google Scholar 

  27. O’Hara MH, O’Reilly EM, Varadhachary G, Wolff RA, Wainberg ZA, Ko AH, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. Lancet Oncol. 2021;22:118–31.

    Article  Google Scholar 

  28. Byrne KT, Betts CB, Mick R, Sivagnanam S, Bajor DL, Laheru DA, et al. Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer. Clin Cancer Res. 2021;27:4574–86.

    Article  CAS  Google Scholar 

  29. Oh DY, He AR, Qin S, Chen LT, Okusaka T, Vogel A, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. J Clin Oncol. 2022;40:378.

    Article  Google Scholar 

  30. Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. Clin Cancer Res. 2020;26:2124–30.

    Article  CAS  Google Scholar 

  31. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    Article  CAS  Google Scholar 

  32. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905.

    Article  CAS  Google Scholar 

  33. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77–90.

    Article  CAS  Google Scholar 

  34. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol. 2020;38:193–202.

    Article  CAS  Google Scholar 

  35. Abou-Alfa GK, Chan SL, Kudo M, Lau G, Kelley RK, Furuse J, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022;40(4 Suppl):379.

    Article  Google Scholar 

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Acknowledgments

The investigators were supported by NIH grants R01 CA102613 and T32 CA251063.

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Authors and Affiliations

  1. Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Andrew D. Tieniber MD, Juanes E. Perez MD, Andrew N. Hanna MD & Ronald P. DeMatteo MD

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Correspondence to Ronald P. DeMatteo MD.

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Tieniber, A.D., Perez, J.E., Hanna, A.N. et al. Immunotherapy for GI Malignancies, Ready for Prime Time?. Ann Surg Oncol 30, 1787–1793 (2023). https://doi.org/10.1245/s10434-022-12668-w

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