Review Article

Immune Checkpoint Inhibition for Pancreatic Cancer

Abstract

Pancreatic cancer is one of the ten most lethal cancers with a mortality rate of 5.7 per 100,000 individuals worldwide. According to the disease stage, its 5-year survival rate is between 3% and 34%. Treatment options for pancreatic cancer are surgery, chemotherapy, radiotherapy, and immunotherapy. Immune checkpoint inhibitor therapy is a kind of immunotherapy. Immune checkpoints on T cells like cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) suppress the immune system by attaching to their ligands on normal and/or tumor cells. This mechanism protects the body against immune system hyperactivity, especially in autoimmune diseases, but tumor cells can escape from immune responses by expressing these ligands to maintain in the body and to be safe against the immune system. Immune checkpoint inhibitors are immunotherapeutic drugs that bind to proteins in cancer cells to prevent them from suppressing the immune system. Immune checkpoint inhibitors may lead to some adverse effects like vitiligo, thyroiditis, adrenal insufficiency, and other ophthalmologic, hematologic, and respiratory problems. However, it has been shown that the combination of these therapies with each other or other therapeutic approaches could increase the safety and efficacy of this developing method. Here, we will review some trials that have been done or are ongoing about the advances and the effects of immune checkpoint inhibitors on patients with pancreatic cancer.

1. Shetty AS O. Rare Pancreatic Tumors. Magn Reson Imaging Clin N Am 2018;26:421-37.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34.
3. Preziosi G, Oben JA, Fusai G. Obesity and pancreatic cancer. Surg Oncol 2014;23:61-71.
4. Alsamarrai A, Das SL, Windsor JA, Petrov MS. Factors that affect risk for pancreatic disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Clin Gastroenterol Hepatol 2014;12:1635-44.e5; quiz e103.
5. Zhao Z, Yin Z, Pu Z, Zhao Q. Association Between Consumption of Red and Processed Meat and Pancreatic Cancer Risk: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2017;15:486-493.e10.
6. Wu QJ, Wu L, Zheng LQ, Xu X, Ji C, Gong TT. Consumption of fruit and vegetables reduces risk of pancreatic cancer: evidence from epidemiological studies. Eur J Cancer Prev 2016;25:196-205.
7. Haseeb A, Siddiqi MJS, Shaikh MF, Bowne WB. Laboratory Diagnosis of Gastrointestinal and Pancreatic Disorders. In: McPherson RA, Pincus MR. Henry's Clinical Diagnosis and Management by Laboratory Methods. 23 ed. New York: Elsevier Inc.; 2016:306-23.
8. Mukesh MGH, Harisinghani JWC, Weissleder R. Gastrointestinal Imaging. In: Mukesh MGH, Harisinghani JWC, Weissleder R, eds. Primer of Diagnostic Imaging. Amsterdam, Netherlands: Elsevier; 2018:124-216.
9. Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol 2012;26:737-53.
10. Nentwich MF, Bockhorn M, Konig A, Izbicki JR, Cataldegirmen G. Surgery for advanced and metastatic pancreatic cancer--current state and trends. Anticancer Res 2012;32:1999-2002.
11. Jilesen AP, van Eijck CH, Busch OR, van Gulik TM, Gouma DJ, van Dijkum EJ. Postoperative Outcomes of Enucleation and Standard Resections in Patients with a Pancreatic Neuroendocrine Tumor. World J Surg 2016;40:715-28.
12. Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996;7:593-600.
13. Catenacci DV, Junttila MR, Karrison T, Bahary N, Horiba MN, Nattam SR, et al. Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer. J Clin Oncol 2015;33:4284-92.
14. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018;379:2395-406.
15. Attard CL, Brown S, Alloul K, Moore MJ. Cost-effectiveness of FOLFIRINOX for first-line treatment of metastatic pancreatic cancer. Curr Oncol 2014;21:e41-51.
16. Conroy T, Desseigne F, Ychou M, Ducreux M, Bouche O, Guimbaud R, et al. Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ACCORD 11 trial. J Clin Oncol 2010;28:4010.
17. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-6.
18. Rubinson DA, Wolpin BM. Therapeutic Approaches for Metastatic Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am 2015;29:761-76.
19. Rombouts SJ, Mungroop TH, Heilmann MN, van Laarhoven HW, Busch OR, Molenaar IQ, et al. FOLFIRINOX in Locally Advanced and Metastatic Pancreatic Cancer: A Single Centre Cohort Study. J Cancer 2016;7:1861-6.
20. Sherman WH, Chu K, Chabot J, Allendorf J, Schrope BA, Hecht E, et al. Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma. Cancer 2015;121:673-80.
21. Khorana AA, Mangu PB, Berlin J, Engebretson A, Hong TS, Maitra A, et al. Potentially Curable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2017;35:2324-8.
22. Boothe D, Clyde JW, Christensen M, Patel SB, Lloyd S. A comprehensive analysis of clinical trials including both immunotherapy and radiation therapy. J Radiat Oncol 2018;7:223-32.
23. Goodman KA, Hajj C. Role of radiation therapy in the management of pancreatic cancer. J Surg Oncol 2013;107:86-96.
24. Reese AS, Lu W, Regine WF. Utilization of intensity-modulated radiation therapy and image-guided radiation therapy in pancreatic cancer: is it beneficial? Semin Radiat Oncol 2014;24:132-9.
25. Jung J, Yoon SM, Park JH, Seo DW, Lee SS, Kim MH, et al. Stereotactic body radiation therapy for locally advanced pancreatic cancer. PloS one 2019;14:e0214970.
26. Jethwa KR, Tryggestad EJ, Whitaker TJ, Giffey BT, Kazemba BD, Neben-Wittich MA, et al. Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: Clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. Adv Radiat Oncol 2018;3:314-21.
27. Ceha HM, van Tienhoven G, Gouma DJ, Veenhof CH, Schneider CJ, Rauws EA, et al. Feasibility and efficacy of high dose conformal radiotherapy for patients with locally advanced pancreatic carcinoma. Cancer 2000;89:2222-9.
28. Ben-Josef E, Schipper M, Francis IR, Hadley S, Ten-Haken R, Lawrence T, et al. A Phase I/II Trial of Intensity Modulated Radiation (IMRT) Dose Escalation With Concurrent Fixed-dose Rate Gemcitabine (FDR-G) in Patients With Unresectable Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2012;84:1166-71.
29. Sideras K, Braat H, Kwekkeboom J, van Eijck CH, Peppelenbosch MP, Sleijfer S, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat Rev 2014;40:513-22.
30. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017;377:1824-35.
31. Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer 2019;22:828-37.
32. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389:67-76.
33. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D'Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:1374-85.
34. Tawbi HA, Forsyth PA, Algazi A, Hamid O, Hodi FS, Moschos SJ, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018;379:722-30.
35. Varga A, Piha-Paul S, Ott PA, Mehnert JM, Berton-Rigaud D, Morosky A, et al. Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Gynecol Oncol 2019;152:243-50.
36. Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol 2018;19:1468-79.
37. Laplagne C, Domagala M, Le Naour A, Quemerais C, Hamel D, Fournie JJ, et al. Latest Advances in Targeting the Tumor Microenvironment for Tumor Suppression. Int J Mol Sci 2019;20:4719.
38. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006;12:5423-34.
39. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 2011;60:1419-30.
40. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004;57:630-6.
41. Aparicio-Pages MN, Verspaget HW, Pena AS, Lamers CB. Natural killer cell activity in patients with adenocarcinoma in the upper gastrointestinal tract. J Clin Lab Immunol 1991;35:27-32.
42. Banerjee K, Kumar S, Ross KA, Gautam S, Poelaert B, Nasser MW, et al. Emerging trends in the immunotherapy of pancreatic cancer. Cancer Lett 2018;417:35-46.
43. Dubbs SB. The Latest Cancer Agents and Their Complications. Emerg Med Clin North Am 2018;36:485-92.
44. Narvaez J, Juarez-Lopez P, LLuch J, Narvaez JA, Palmero R, Garcia Del Muro X, et al. Rheumatic immune-related adverse events in patients on anti-PD-1 inhibitors: Fasciitis with myositis syndrome as a new complication of immunotherapy. Autoimmun Rev 2018;17:1040-5.
45. Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2017;18:153-67.
46. Marin-Acevedo JA, Chirila RM, Dronca RS. Immune Checkpoint Inhibitor Toxicities. Mayo Clin Proc 2019;94:1321-9.
47. Fujii T, Naing A, Rolfo C, Hajjar J. Biomarkers of response to immune checkpoint blockade in cancer treatment. Crit Rev Oncol Hematol 2018;130:108-20.
48. Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, et al. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J Cancer Res Clin Oncol 2008;134:1021-7.
49. 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;20:5064-74.
50. Kelderman S, Heemskerk B, Van Tinteren H, Van Den Brom RRH, Hospers GAP, Van Den Eertwegh AJM, et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 2014;63:449-58.
51. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497-508.
52. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz H-J, Morse MA, et al. 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;18:1182-91.
53. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-20.
54. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23.
55. Johnson DB, Chandra S, Sosman JA. Immune Checkpoint Inhibitor Toxicity in 2018. JAMA 2018;320:1702-3.
56. Liu Y, Zheng P. How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity? Trends Immunol 2018;39:953-6.
57. Binder KR. Niraparib + Ipilimumab or Nivolumab in Progression Free Pancreatic Adenocarcinoma After Platinum-Based Chemotherapy (Parpvax). (Accessed April 11, 2023, at https://clinicaltrials.gov/ct2/show/NCT03404960.)
58. Chen I. Immune Checkpoint Inhibition in Combination With Radiation Therapy in Pancreatic Cancer or Biliary Tract Cancer Patients. (Accessed September 5, 2020, at https://clinicaltrials.gov/ct2/show/NCT02866383.)
59. Patel S. Nivolumab and Ipilimumab in Treating Patients With Rare Tumors (Accessed March 30, 2023, at https://clinicaltrials.gov/ct2/show/NCT02834013.)
60. La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB. Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy 2015;35:963-76.
61. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373:1803-13.
62. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492-502.
63. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015;373:123-35.
64. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18:312-22.
65. Ugwu JK, Nwanyanwu C, Shelke AR. Dramatic Response of a Metastatic Primary Small-Cell Carcinoma of the Pancreas to a Trial of Immunotherapy with Nivolumab: A Case Report. Case Rep Oncol 2017;10:720-5.
66. Costa RB, Al B, Yaghmai V, Costa RLB, Zhou HJ, Behdad A, et al. An Extremely Rapid Case of Pneumonitis with the Use of Nivolumab for Pancreatic Adenocarcinoma. Case Rep Oncol Med 2018;2018:6314392.
67. Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, et al. Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. Clin Lung Cancer. 2018;19:e861-4.
68. Lynch C. Study of Nivolumab Plus Chemotherapy in Patients With Advanced Cancer (NivoPlus). (Accessed July 2, 2018, at https://clinicaltrials.gov/ct2/show/study/NCT02423954.)
69. Lead M. Study of Cabiralizumab in Combination With Nivolumab in Patients With Selected Advanced Cancers (Accessed March 9, 2022, https://clinicaltrials.gov/ct2/show/study/NCT02526017.)
70. Hong T. Nivolumab and Ipilimumab and Radiation Therapy in MSS and MSI High Colorectal and Pancreatic Cancer (Accessed September 8, 2022, https://clinicaltrials.gov/ct2/show/NCT03104439).
71. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol 2017;35:2125-32.
72. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-50.
73. Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956-65.
74. Fuchs CS, Doi T, Jang RWJ, Muro K, Satoh T, Machado M, et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 2017;35:4003.
75. Weiss GJ, Waypa J, Blaydorn L, Coats J, McGahey K, Sangal A, et al. A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Br J Cancer 2017;117:33-40.
76. Weiss GJ, Blaydorn L, Beck J, Bornemann-Kolatzki K, Urnovitz H, Schutz E, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs 2018;36:96-102.
77. Katz MHG, Varadhachary GR, Bauer TW, Acquavella N, Merchant NB, Le TM, et al. Preliminary safety data from a randomized multicenter phase Ib/II study of neoadjuvant chemoradiation therapy (CRT) alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic cancer. J Clin Oncol 2017;35:4125.
78. Slingluff CL. Safety and Immunological Effect of Pembrolizumab in Resectable or Borderline Resectable Pancreatic Cancer (UVA-PC-PD101). (Accessed August 13, 2021, at https://clinicaltrials.gov/ct2/show/study/NCT02305186.)
79. Lederhandler MH, Ho A, Brinster N, Ho RS, Liebman TN, Lo Sicco K. Severe Oral Mucositis: A Rare Adverse Event of Pembrolizumab. J Drugs Dermatol 2018;17:807-9.
80. Fogelman D. Pembrolizumab and BL-8040 in Metastatic Pancreatic Cancer (Accessed March 9, 2023, at https://clinicaltrials.gov/ct2/show/study/NCT02907099.)
81. Goldstein J, Katz M. Preoperative Pilot Study to Assess Safety and Immunological Effect of Pembrolizumab (Keytruda®) in Combination With Paricalcitol With or Without Chemotherapy in Patients With Resectable Pancreatic Cancer. (Accessed February 9, 2023, https://clinicaltrials.gov/ct2/show/NCT02930902.)
82. Borazanci E, Jameson G, Chung V, Alistar A, Hoff DDV. A SU2C Catalyst® Trial of a PD1 Inhibitor With or Without a Vitamin D Analog for the Maintenance of Pancreatic Cancer. (Accessed December 27, 2022, at https://clinicaltrials.gov/ct2/show/NCT03331562).
83. Orskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M, et al. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget 2015;6:9612-26.
84. Safyan RA, Gonda T, Tycko B, Chabot JA, Manji GA, Schwartz GK. Phase II open-label, single-center study evaluating safety and efficacy of pembrolizumab following induction with the hypomethylating agent azacitidine in patients with advanced pancreatic cancer after failure of first-line therapy. J Clin Oncol 2018;36:1.
85. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20.
86. Krishnamurthy A, Jimeno A. Atezolizumab: A novel PD-L1 inhibitor in cancer therapy with a focus in bladder and non-small cell lung cancers. Drugs Today (Barc) 2017;53:217-37.
87. Roche HL. A Study of Multiple Immunotherapy-Based Treatment Combinations in Participants With Metastatic Pancreatic Ductal Adenocarcinoma (Morpheus-Pancreatic Cancer). )Accessed April 10, 2023, at https://clinicaltrials.gov/ct2/show/record/NCT03193190).
88. Julia EP, Amante A, Pampena MB, Mordoh J, Levy EM. Avelumab, an IgG1 anti-PD-L1 Immune Checkpoint Inhibitor, Triggers NK Cell-Mediated Cytotoxicity and Cytokine Production Against Triple Negative Breast Cancer Cells. Front Immunol 2018;9:2140.
89. Kelly K, Infante JR, Taylor MH, Patel MR, Wong DJ, Iannotti N, et al. Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer 2018;124:2010-7.
90. Heery CR, O'Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol 2017;18:587-98.
91. Hassan R, Thomas A, Nemunaitis JJ, Patel MR, Bennouna J, Chen FL, et al. Efficacy and Safety of Avelumab Treatment in Patients With Advanced Unresectable Mesothelioma: Phase 1b Results From the JAVELIN Solid Tumor Trial. JAMA Oncol 2019;5:351-7.
92. Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, et al. Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer 2018;6:111.
93. Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 2018;19:51-64.
94. Gulley JL, Rajan A, Spigel DR, Iannotti N, Chandler J, Wong DJL, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18:599-610.
95. Rodriguez LM, Batle JF, Ponce CG. A Trial of PEGPH20 in Combination With Avelumab in Chemotherapy Resistant Pancreatic Cancer. (Accessed August 22, 2019, at https://clinicaltrials.gov/ct2/show/study/NCT03481920.)
96. Bahary N. Pre-Operative Trial (PGHA vs. PGH) for Resectable Pancreatic Cancer (17-134). (Accessed May 14, 2020, https://clinicaltrials.gov/ct2/show/study/NCT03344172.)
97. 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;36:382-9.
98. Morse MA, Lyerly HK. Checkpoint blockade in combination with cancer vaccines. Vaccine 2015;33:7377-85.
99. Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19:1480-92.
100. Gray JE, Chiappori A, Williams CC, Tanvetyanon T, Haura EB, Creelan BC, et al. A phase I/randomized phase II study of GM.CD40L vaccine in combination with CCL21 in patients with advanced lung adenocarcinoma. Cancer Immunol Immunother 2018;67:1853-62.
101. 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;18:332.
102. Emens LA. Cancer vaccines: on the threshold of success. Expert opinion on emerging drugs. Expert Opin Emerg Drugs 2008;13:295-308.
103. Maeng H, Terabe M, Berzofsky JA. Cancer vaccines: translation from mice to human clinical trials. Curr Opin Immunol 2018;51:111-22.
104. 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.
105. Mahalingam D. Pembrolizumab and Pelareorep in Treating Patients With Advanced Pancreatic Cancer. (Accessed October 5, 2022, https://clinicaltrials.gov/ct2/show/record/NCT03723915.)
106. Noonan AM, Farren MR, Geyer SM, Huang Y, Tahiri S, Ahn D, et al. Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma. Mol Ther 2016;24:1150-8.
107. Chen J, Chen L, Yu J, Xu Y, Wang X, Zeng Z, et al. Metaanalysis of current chemotherapy regimens in advanced pancreatic cancer to prolong survival and reduce treatmentassociated toxicities. Mol Med Rep 2019;19:477-89.


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IssueVol 61 No 3 (2023) QRcode
SectionReview Article(s)
DOI https://doi.org/10.18502/acta.v61i3.12735
Keywords
Immune checkpoint inhibitors Pancreatic cancer Immunotherapy Cluster of differentiation 152 (CD152) Cluster of differentiation 279 (CD279) Cluster of differentiation 274 (CD274)

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Nejadghaderi SA, Razi S, Keshavarz athi M, Rezaei N. Immune Checkpoint Inhibition for Pancreatic Cancer. Acta Med Iran. 2023;61(3):128-144.