Combination immunotherapy for pancreatic cancer: challenges and future considerations

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–249.
   PubMed Web of Science ®Google Scholar
• Rahib L, Wehner MR, Matrisian LM, et al. Estimated projection of US cancer incidence and death to 2040. JAMA Network Open. 2021;4(4):e214708.
   PubMed Web of Science ®Google Scholar
• Tempero MA, Malafa MP, Al-Hawary M, et al. Pancreatic adenocarcinoma, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(4):439–457.
   PubMed Web of Science ®Google Scholar
• Shibuya KC, Goel VK, Xiong W, et al. Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment. PLoS One. 2014;9(5):e96565.
   PubMed Web of Science ®Google Scholar
• Schmitz-Winnenthal FH, Volk C, Z’graggen K, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res. 2005;65(21):10079–10087.
   PubMed Web of Science ®Google Scholar
• Fukunaga A, Miyamoto M, Cho Y, et al. CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28(1):e26–31.
   PubMed Web of Science ®Google Scholar
• Balachandran VP, Łuksza M, Zhao JN, et al., Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017;551(7681):S12–16.
   Web of Science ®Google Scholar
• Bear AS, Vonderheide RH, O’Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802.
   PubMed Web of Science ®Google Scholar
• Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377(25):2500–2501.
   PubMed Web of Science ®Google Scholar
• Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24:541–550.
   PubMed Web of Science ®Google Scholar
• McCormick KA, Coveler AL, Rossi GR, et al. Pancreatic cancer: update on immunotherapies and algenpantucel-L. Hum Vaccin Immunother. 2016;12(3):563–575.
   PubMed Web of Science ®Google Scholar
• Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157.
   PubMed Web of Science ®Google Scholar
• Kraman M, Bambrough PJ, Arnold JN, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-a. Science. 2010;330(6005):827–830.
   PubMed Web of Science ®Google Scholar
• Feig C, Jones JO, Kraman M, et al., Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PDL1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci. 2013;110(50):20212–20217.
   PubMed Web of Science ®Google Scholar
• Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2(3):187–193.
   PubMed Web of Science ®Google Scholar
• Marabelle A, Le DT, Ascierto PA, 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):1–10.
   PubMed Web of Science ®Google Scholar
• Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (Anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–833.
   PubMed Web of Science ®Google Scholar
• Patnaik A, Kang SP, Rasco D, et al. Phase I study of Pembrolizumab (MK-3475; Anti–PD-1 monoclonal antibody) in patients with advanced solid tumors. Clin Cancer Res. 2015;21(19):4286–4293.
   PubMed Web of Science ®Google Scholar
• Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced Cancer. N Engl J Med. 2012;366(26):2455–2465.
   PubMed Web of Science ®Google Scholar
• O’Reilly EM, Oh DY, Dhani N, et al., Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(10):1431–1438.
   PubMed Web of Science ®Google Scholar
• Jiang J, Zhou H, Ni C, et al. Immunotherapy in pancreatic cancer: new hope or mission impossible? Cancer Lett. 2019;445:57–64.
   PubMed Web of Science ®Google Scholar
• Soares KC, Rucki AA, Wu AA, 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.
   PubMed Web of Science ®Google Scholar
• Castle JC, Uduman M, Pabla S, et al. Mutation‐derived neoantigens for cancer immunotherapy. Front Immunol. 2019;10:1856.
   PubMed Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.
   PubMed Web of Science ®Google Scholar
• Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203(5):1259–1271.
   PubMed Web of Science ®Google Scholar
• Ngwa W, Irabor OC, Schoenfeld JD, et al. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313–322.
   PubMed Web of Science ®Google Scholar
• Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade. Clin Cancer Res. 2017;23(18):5514–5526.
   PubMed Web of Science ®Google Scholar
• Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050–1059.
   PubMed Web of Science ®Google Scholar
• Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation- induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41(5):843–852.
   PubMed Web of Science ®Google Scholar
• Wainberg ZA, Hochster HS, Kim EJ, et al. Open-label, phase I study of nivolumab combined with nab -paclitaxel plus gemcitabine in advanced pancreatic cancer. Clin Cancer Res. 2020;26(18):4814–4822.
   PubMed Web of Science ®Google Scholar
• O’Hara MH, O’Reilly EM, Varadhachary G, 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(1):118–131.
   PubMed Web of Science ®Google Scholar
• Weiss GJ, Blaydorn L, Beck J, et al. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest New Drugs. 2018;36(1):96–102.
   PubMed Web of Science ®Google Scholar
• Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–1703.
   PubMed Web of Science ®Google Scholar
• Fu Q, Chen Y, Huang D, et al. Randomized phase III study of sintilimab in combination with modified folfrinox versus folfrinox alone in patients with metastatic and recurrent pancreatic cancer in China: the CISPD3 trial. J Clin Oncol. 2022;40(4_suppl):560. suppl abstr 560.
   Web of Science ®Google Scholar
• Ueno M, Morizane C, Ikeda M, et al. A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer. J Clin Oncol. 2022;40(4_suppl):553. suppl abstr 553.
   Web of Science ®Google Scholar
• Ramanathan RK, McDonough SL, Philip PA, et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J Clin Oncol. 2019;37(13):1062–1069.
   PubMed Web of Science ®Google Scholar
• Renouf D, Knox JJ, Kavan P, et al. The Canadian cancer trials group PA.7 trial: results of a randomized phase II study of gemcitabine and nab-paclitaxel vs gemcitabine, nab-paclitaxel, durvalumab and tremelimumab as first line therapy in metastatic pancreatic ductal adenocarcinoma. Ann Oncol. 2020;suppl abstr LBA65.31:S1195.
   Web of Science ®Google Scholar
• Renouf DJ, Loree JM, Knox JJ, et al. Predictive value of plasma tumor mutation burden (TMB) in the CCTG PA.7 trial: gemcitabine and nab-paclitaxel versus gemcitabine, nab-paclitaxel, durvalumab and tremelimumab as first-line therapy in metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2021;39(3_suppl):411.
   Web of Science ®Google Scholar
• Renouf DJ, Loree JM, Knox JJ, et al. Predictive value of germline ATM mutations in the CCTG PA.7 trial: gemcitabine and nab-paclitaxel versus gemcitabine, nab-paclitaxel, durvalumab and tremelimumab as first-line therapy in metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2021;39(3_suppl):4135.
   Web of Science ®Google Scholar
• Parikh A, Jyl W, Ryan DP, et al. A phase II study of ipilimumab and nivolumab with radiation in metastatic pancreatic adenocarcinoma. J Clin Oncol. 2019;37(15_suppl):3514. suppl abstr 391.
   Google Scholar
• Xie C, Duffy AG, Brar G, et al. Immune checkpoint blockade in combination with stereotactic body radiotherapy in patients with metastatic pancreatic ductal adenocarcinoma. Clin Cancer Res. 2020;26(10):2318–2326.
   PubMed Web of Science ®Google Scholar
• Chen IM, Johansen JS, Theile S, et al. Randomized phase 2 study of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy in patients with refractory metastatic pancreatic cancer (CHECKPAC). J Clin Oncol. 2022;40(4_suppl):554.
   Web of Science ®Google Scholar
• Le DT, Picozzi VJ, Ko AH, 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(18):5493–5502.
   PubMed Web of Science ®Google Scholar
• King G, Green S, Chiorean EG. Finding a role for cancer vaccines in pancreatic cancer: a model of resilience. Hepatobiliary Surg Nutr. 2022;11(1):115–118.
   PubMed Web of Science ®Google Scholar
• Lutz ER, Wu AA, Bigelow E, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014;2(7):616–631.
   PubMed Web of Science ®Google Scholar
• Le DT, Lutz E, Uram JN, 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):382–389.
   PubMed Web of Science ®Google Scholar
• Wu AA, Bever KM, Ho WJ, et al. A Phase II study of allogeneic GM-CSF-transfected pancreatic tumor vaccine (GVAX) with ipilimumab as maintenance treatment for metastatic pancreatic cancer. Clin Cancer Res. 2020;26(19):5129–5139.
   PubMed Web of Science ®Google Scholar
• Tsujikawa T, Crocenzi T, Durham JN, 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(14):3578–3588.
   PubMed Web of Science ®Google Scholar
• Gatti-Mays ME, Strauss J, Donahue RN, et al. A Phase I dose-escalation trial of BN-CV301, a recombinant poxviral vaccine targeting MUC1 and CEA with costimulatory molecules. Clin Cancer Res. 2019;25(16):4933–4944.
   PubMed Web of Science ®Google Scholar
• Muth ST, Saung MT, Blair AB, et al. CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma. Cancer Lett. 2021;499:99–108.
   PubMed Web of Science ®Google Scholar
• Ma Y, Li J, Wang H, et al. Combination of PD-1 inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic cancer. Gastroenterology. 2020;159(1):306–319.
   PubMed Web of Science ®Google Scholar
• Zheng L, Judkins C, Hoare J, et al. Urelumab (anti-CD137 agonist) in combination with vaccine and nivolumab treatments is safe and associated with pathologic response as neoadjuvant and adjuvant therapy for resectable pancreatic cancer. J Immunother Cancer. 2020;8:abstr 812.
   Web of Science ®Google Scholar
• Fountzilas C, Patel S, Mahalingam D. Review: oncolytic virotherapy, updates and future directions. Oncotarget. 2017;8(60):102617–102639.
   PubMedGoogle Scholar
• Mahalingam D, Goel S, Aparo S, et al. A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers (Basel). 2018;10(6):160.
   PubMed Web of Science ®Google Scholar
• Mahalingam D, Wilkinson GA, Eng KH, et al. Pembrolizumab in combination with the oncolytic virus pelareorep and chemotherapy in patients with advanced pancreatic adenocarcinoma: a phase Ib study. Clin Cancer Res. 2020;26(1):71–81.
   PubMed Web of Science ®Google Scholar
• Bazan-Peregrino M, Garcia-Carbonero R, Laquente B, et al. VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects. J Immunother Cancer. 2021;9(11):e003254.
   PubMed Web of Science ®Google Scholar
• Garcia-Carbonero R, Bazan-Peregrino M, Gil-Martín M, et al. Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors. J Immunother Cancer. 2022;10(3):e003255.
   PubMed Web of Science ®Google Scholar
• Hirooka Y, Kasuya H, Ishikawa T, et al. A phase I clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer. BMC Cancer. 2018;18(1):1–9.
   PubMedGoogle Scholar
• Vonderheide RH. CD40 agonist antibodies in cancer immunotherapy. Annu Rev Med. 2020;71(1):47–58.
   PubMed Web of Science ®Google Scholar
• Elgueta R, Benson MJ, De Vries VC, et al. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009;229(1):152–172.
   PubMed Web of Science ®Google Scholar
• Zippelius A, Schreiner J, Herzig P, et al. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3(3):236–244.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Chiorean EG, Fishman MP, et al., CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–1616.
   PubMed Web of Science ®Google Scholar
• Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19(22):6286–6295.
   PubMed Web of Science ®Google Scholar
• O’Hara MH, O’Reilly EM, Wolff RA, et al. Gemcitabine and nab-paclitaxel ± nivolumab ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients with untreated metastatic pancreatic adenocarcinoma: phase 2 final results. J Clin Oncol. 2021;39(3_suppl):4019.
   Web of Science ®Google Scholar
• Byrne KT, Betts CB, Mick R, et al. Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer.
   Google Scholar
• Oba T, Long MD, Keler T, et al. Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s. Nat Commun. 2020;11(1):5415.
   PubMed Web of Science ®Google Scholar
• Sanborn R, Hauke R, Gabrail N, et al. 405 CDX1140–01, a phase 1 dose-escalation/ expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3). J Immunother Cancer. 2020;8: 10.1136/jitc-2020-SITC2020. 0405.
   Web of Science ®Google Scholar
• O’Reilly EM, Lee JW, Zalupski M, et al. Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a Germline BRCA/PALB2 mutation. J Clin Oncol. 2020;38(13):1378–1388.
   PubMed Web of Science ®Google Scholar
• Chiorean EG, Guthrie KA, Philip PA, et al. Randomized phase II study of PARP inhibitor ABT-888 (Veliparib) with modified FOLFIRI versus FOLFIRI as second-line treatment of metastatic pancreatic cancer: SWOG S1513. Clin Cancer Res. 2021;27(23):6314–6322.
   PubMed Web of Science ®Google Scholar
• Golan T, Hammel P, Reni M, et al. Maintenance olaparib for Germline BRCA -mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317–327.
   PubMed Web of Science ®Google Scholar
• Reiss KA, Mick R, O’Hara MH, et al. Phase II Study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic Germline or somatic variant in BRCA1, BRCA2, or PALB2. J Clin Oncol. 2021;39(22):2497–2505.
   PubMed Web of Science ®Google Scholar
• Vikas P, Borcherding N, Chennamadhavuni A, et al. Therapeutic potential of combining PARP inhibitor and immunotherapy in solid tumors. Front Oncol. 2020;10:570.
   PubMed Web of Science ®Google Scholar
• Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711–3720.
   PubMed Web of Science ®Google Scholar
• Topper MJ, Vaz M, Marrone KA, et al. The emerging role of epigenetic therapeutics in immuno-oncology. Nat Rev Clin Oncol. 2020;17(2):75–90.
   PubMed Web of Science ®Google Scholar
• Christmas BJ, Rafie CI, Hopkins AC, et al. Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res. 2018;6(12):1561–1577.
   PubMed Web of Science ®Google Scholar
• Algaze S, Hanna DL, Azad NS, et al. A phase Ib study of guadecitabine and durvalumab in patients with advanced hepatocellular carcinoma, pancreatic adenocarcinoma, and biliary cancers. J Clin Oncol. 2022;suppl 40(4_suppl):abstr 574.
   Web of Science ®Google Scholar
• Yamamoto K, Venida A, Yano J, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020;581(7806):100–105.
   PubMed Web of Science ®Google Scholar
• Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al. Effect of gemcitabine and nab-paclitaxel with or without hydroxychloroquine on patients with advanced pancreatic cancer: a phase 2 randomized clinical trial. JAMA Oncol. 2019;5(7):993–998.
   PubMed Web of Science ®Google Scholar
• Bryant KL, Stalnecker CA, Zeitouni D, et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med. 2019;25(4):628–640.
   PubMed Web of Science ®Google Scholar
• Hogquist KA, Baldwin TA, Jameson SC. Central tolerance: learning self-control in the thymus. Nat Rev Immunol. 2005;5(10):772–782.
   PubMed Web of Science ®Google Scholar
• June C, Rosenberg SA, Sadelain M, et al. T-cell therapy at the threshold. Nat Biotechnol. 2012;30(7):611–614.
   PubMed Web of Science ®Google Scholar
• Stromnes IM ST, Chapuis AG, Hingorani SR, et al., Re-adapting T cells for cancer therapy: from mouse models to clinical trials. Immunol Rev. 2014;257(1):145–164.
   PubMed Web of Science ®Google Scholar
• Beatty GL, O’Hara MH, Lacey SF, et al., Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155(1):29–32.
   PubMed Web of Science ®Google Scholar
• Liu Y, Guo Y, Wu Z, et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: a phase I clinical trial. Cytotherapy. 2020;22(10):573–580.
   PubMed Web of Science ®Google Scholar
• Wang Y, Chen M, Wu Z, et al. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. Oncoimmunology. 2018;7(7):e1440169.
   PubMed Web of Science ®Google Scholar
• Yeo D, Giardina C, Saxena P, et al. The next wave of cellular immunotherapies in pancreatic cancer. Mol Ther Oncolytics. 2022;24:561–576.
   PubMed Web of Science ®Google Scholar
• Lesch S, Blumenberg V, Stoiber S, et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat Biomed Eng. 2021;5(11):1246–1260.
   PubMed Web of Science ®Google Scholar
• Ko AH, Jordan AC, Tooker E, et al. Dual targeting of mesothelin and CD19 with chimeric antigen receptor-modified T cells in patients with metastatic pancreatic cancer. Mol Ther. 2020;28(11):2367–2378.
   PubMed Web of Science ®Google Scholar
• Yang C-Y, Fan MH, Miao CH, et al. Engineering chimeric antigen receptor T cells against immune checkpoint inhibitors PD-1/PD-L1 for treating pancreatic cancer. Mol Ther Oncolytics. 2020;17:571–585.
   PubMed Web of Science ®Google Scholar
• McGrath K, Dotti G. Combining oncolytic viruses with chimeric antigen receptor T cell therapy. Hum Gene Ther. 2021;32(3–4):150–157.
   PubMed Web of Science ®Google Scholar
• Leidner R, Sanjuan Silva N, Huang H, et al., Neoantigen T-cell receptor gene therapy in pancreatic cancer. N Engl J Med. 2022;386(22):2112–2119.
   PubMed Web of Science ®Google Scholar
• Seery T, Nangia C, McKean H, et al. Promising survival and disease control in third-line or greater metastatic or locally advanced pancreatic cancer patients following chemo-radiation and novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy. J Clin Oncol. 2022;40(4_suppl):TPS582.
   Web of Science ®Google Scholar
• Sleightholm RL, Neilsen BK, Li J, et al. Emerging roles of the CXCL12/CXCR4 axis in pancreatic cancer progression and therapy. Pharmacol Ther. 2017;179:158–170.
   PubMed Web of Science ®Google Scholar
• Sanford DE, Belt BA, Panni RZ, et al. Inflammatory monocyte mobilization decreases patient survival in pancreatic cancer: a role for targeting the CCL2/CCR2 axis. Clin Cancer Res. 2013;19(13):3404–3415.
   PubMed Web of Science ®Google Scholar
• Steele CW, Karim SA, Leach JDG, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29(6):832–845.
   PubMed Web of Science ®Google Scholar
• Seo YD, Jiang X, Sullivan KM, et al. Mobilization of0020CD8+ T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Clin Cancer Res. 2019;25(13):3934–3945.
   PubMed Web of Science ®Google Scholar
• Bockorny B, Semenisty V, Macarulla T, et al., BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med. 2020;26(6):878–885.
   PubMed Web of Science ®Google Scholar
• Bockorny B, Macarulla T, Semenisty V, et al. Motixafortide and pembrolizumab combined to nanoliposomal irinotecan, fluorouracil, and folinic acid in metastatic pancreatic cancer: the COMBAT/KEYNOTE-202 trial. Clin Cancer Res. 2021;27(18):5020–5027.
   PubMed Web of Science ®Google Scholar
• Suarez-Carmona M, Williams A, Schreiber J, et al. Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects. J Immunother Cancer. 2021;9(10):e002505.
   PubMed Web of Science ®Google Scholar
• Nywening TM, Belt BA, Cullinan DR, et al., Targeting both tumour-associated CXCR2 + neutrophils and CCR2 + macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut. 2018;67(6):1112–1123.
   PubMed Web of Science ®Google Scholar
• Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73(3):1128–1141.
   PubMed Web of Science ®Google Scholar
• Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17(5):651–662.
   PubMed Web of Science ®Google Scholar
• Chao T, Furth EE, Vonderheide RH. CXCR2-dependent accumulation of tumor-associated neutrophils regulates T-cell immunity in pancreatic ductal adenocarcinoma. Cancer Immunol Res. 2016;4(11):968–982.
   PubMed Web of Science ®Google Scholar
• Lianyuan T, Gang L, Ming T, et al. Tumor associated neutrophils promote the metastasis of pancreatic ductal adenocarcinoma. Cancer Biol Ther. 2020;21(10):937–945.
   PubMed Web of Science ®Google Scholar
• Dunne RF, Ullman NA, Belt BA, et al. A phase I study to evaluate the safety and tolerability of SX-682 in combination with PD-1 inhibitor as maintenance therapy for unresectable pancreatic adenocarcinoma. J Clin Oncol. 2022;40(4_suppl):TPS631. suppl abstr TPS631.
   Web of Science ®Google Scholar
• Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418–429.
   PubMed Web of Science ®Google Scholar
• Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018;36(4):359–366.
   PubMed Web of Science ®Google Scholar
• Van Cutsem E, Tempero MA, Sigal D, et al. HALO 109-301 investigators. Randomized phase III trial of pegvorhyaluronidase alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J Clin Oncol. 2020;38(27):3185–3194.
   PubMed Web of Science ®Google Scholar
• Zhen DB, Whittle M, Ritch PS, et al. Phase II study of PEGPH20 plus pembrolizumab for patients with hyaluronan (HA)-high refractory metastatic pancreatic adenocarcinoma: PCRT16-001. J Clin Oncol. 2022;40(4_suppl):576. suppl, abstr 576.
   PubMed Web of Science ®Google Scholar
• Boyd LNC, Andini KD, Peters GJ, et al. Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment. Semin Cancer Biol. 2021;82:SS1044–0.
   Web of Science ®Google Scholar
• Wang LC, Lo A, Scholler J, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2(2):154–166.
   PubMed Web of Science ®Google Scholar
• Watabe T, Liu Y, Kaneda-Nakashima K, et al. Theranostics targeting fibroblast activation protein in the tumor stroma: 64 Cu- and 225 Ac-Labeled FAPI-04 in pancreatic cancer xenograft mouse models. J Nucl Med. 2020;61(4):563–569.
   PubMed Web of Science ®Google Scholar
• Nugent FW, Cunningham C, Barve MA, et al. Phase 2 study of talabostat/gemcitabine in stage IV pancreatic cancer. J Clin Oncol. 2007 18 suppl, 4616 abstr25;2518_suppl:4616
   PubMedGoogle Scholar
• Baum RP, Schuchardt C, Singh A, et al. Feasibility, biodistribution, and preliminary dosimetry in peptide-targeted radionuclide therapy of diverse adenocarcinomas using 177 Lu-FAP-2286: first-in-humans results. J Nucl Med. 2022;63(3):415–423.
   PubMed Web of Science ®Google Scholar
• Friess H, Yamanaka Y, Büchler M, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;105(6):1846–1856.
   PubMed Web of Science ®Google Scholar
• Principe DR, DeCant B, Mascariñas E, et al. TGFβ signaling in the pancreatic tumor microenvironment promotes fibrosis and immune evasion to facilitate tumorigenesis. Cancer Res. 2016;76(9):2525–2539.
   PubMed Web of Science ®Google Scholar
• Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544–548.
   PubMed Web of Science ®Google Scholar
• Dodagatta-Marri E, Meyer DS, Reeves MQ, et al. α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer. 2019;7(1):62.
   PubMed Web of Science ®Google Scholar
• Schlingensiepen KH, Jaschinski F, Lang SA, et al. Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer. Cancer Sci. 2011;102(6):1193–1200.
   PubMed Web of Science ®Google Scholar
• Hong E, Park S, Ooshima A, et al. Inhibition of TGF-β signaling in combination with nal-IRI plus 5-Fluorouracil/Leucovorin suppresses invasion and prolongs survival in pancreatic tumour mouse models. Sci Rep. 2020;10(1):2935.
   PubMed Web of Science ®Google Scholar
• Melisi D, Garcia-Carbonero R, Macarulla T, et al. Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer. Br J Cancer. 2018;119(10):1208–1214.
   PubMed Web of Science ®Google Scholar
• Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5(7):1020–1027.
   PubMed Web of Science ®Google Scholar
• Xie J, Meng Z, Chen L, et al. Phase II study of SHR-1701 combined with famitinib in the treatment of advanced pancreatic cancer or biliary tract cancer. J Clin Oncol. 2022;40(4_suppl):568. suppl abstr 568.
   Web of Science ®Google Scholar
• Heumann T, Azad N. Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance. Cancer Metastasis Rev. 2021;40(3):837–862.
   PubMed Web of Science ®Google Scholar
• Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med. 2016;22(8):851–860.
   PubMed Web of Science ®Google Scholar
• Osipov A, Saung MT, Zheng L, et al. Small molecule immunomodulation: the tumor microenvironment and overcoming immune escape. J Immunother Cancer. 2019;7(1):224.
   PubMed Web of Science ®Google Scholar
• Wang-Gillam A, McWilliams R, Lockhart AC, et al. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: experiences of pancreatic ductal adenocarcinoma patients. Cancer Res. 2020;80(16_Supplement):CT118–CT118. Suppl Abstract CT118.
   Google Scholar
• Zhang D, Li L, Jiang H, et al. Tumor-stroma IL1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res. 2018;78(7):1700–1712.
   PubMed Web of Science ®Google Scholar
• Das S, Shapiro B, Vucic EA, et al. Tumor cell-derived IL1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 2020;80(5):1088–1101.
   PubMed Web of Science ®Google Scholar
• Somani VK, Zhang D, Dodhiawala PB, et al. IRAK4 signaling drives resistance to checkpoint immunotherapy in pancreatic ductal adenocarcinoma. Gastroenterology. 2022;162(7):SS0016–3.
   Web of Science ®Google Scholar
• Winograd R, Simeone DM, Bar-Sagi D. A novel target for combination immunotherapy in pancreatic cancer: IL-1β mediates immunosuppression in the tumor microenvironment. Br J Cancer. 2021;124(11):1754–1756.
   PubMed Web of Science ®Google Scholar
• Oberstein PE, Rahma OE, Beri N, et al. A phase 1b study evaluating IL-1β and PD-1 targeting with chemotherapy in metastatic pancreatic cancer (PanCAN-SR1). J Clin Oncol. 2022;40(4_suppl):557. suppl abstr 557.
   Web of Science ®Google Scholar
• Mace TA, Shakya R, Pitarresi JR, et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2018;67(2):320–332.
   PubMed Web of Science ®Google Scholar
• Akce M, Shaib WL, Diab M, et al. Phase Ib/II trial of siltuximab and spartalizumab in patients with metastatic pancreatic cancer. J Clin Oncol. 2022;40(4_suppl):TPS626. suppl abstr TPS626.
   Web of Science ®Google Scholar
• Bahary N, Wang-Gillam A, Haraldsdottir S, et al. Phase 2 trial of the IDO pathway inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of patients with metastatic pancreas cancer. J Clin Oncol. 2018;36(15_suppl):4015. suppl, abstr 4015.
   Google Scholar
• Jung KH, LoRusso P, Burris H, et al. Phase I study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) administered with PD-L1 inhibitor (atezolizumab) in advanced solid tumors. Clin Cancer Res. 2019;25(11):3220–3228.
   PubMed Web of Science ®Google Scholar
• Young A, Mittal D, Stagg J, et al. Targeting cancer-derived adenosine: new therapeutic approaches. Cancer Discov. 2014;4(8):879–888.
   PubMed Web of Science ®Google Scholar
• Chen Q, Pu N, Yin H, et al. CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer. J Cell Mol Med. 2020;24(15):8674–8686.
   PubMed Web of Science ®Google Scholar
• Le T, Abt E, Kim W, et al. Abstract 6649: inhibiting adenosine signaling and KRAS enhances the effect of α-PD-1 therapy in a KRASG12C/TP53R172H/+ pancreatic cancer model. Cancer Res. 2020;80(16_Supplement):6649. Suppl 6649 abstr.
   Web of Science ®Google Scholar
• Arab S, Hadjati J. Adenosine blockage in tumor microenvironment and improvement of cancer immunotherapy. Immune Netw. 2019;19. 10.4110/in.2019.19.e23
   Web of Science ®Google Scholar
• Manji GA, Wainberg ZA, Krishnan K, et al. ARC-8: phase I/Ib study to evaluate safety and tolerability of AB680 + chemotherapy + zimberelimab (AB122) in patients with treatment-naive metastatic pancreatic adenocarcinoma (mPDAC). J Clin Oncol. 2021;39(3_suppl):abstr 404.
   Web of Science ®Google Scholar
• Fultang L, Panetti S, Ng M, et al. MDSC targeting with gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers. EBioMedicine. 2019;47:235–246.
   PubMed Web of Science ®Google Scholar
• Dominguez GA, Condamine T, Mony S, et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res. 2017;23(12):2942–2950.
   PubMed Web of Science ®Google Scholar
• Tavazoie MF, Pollack I, Tanqueco R, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell. 2018;172(4):825–840.
   PubMed Web of Science ®Google Scholar
• DeNardo DG, Galkin A, Dupont J, et al. GB1275, a first-in-class CD11b modulator: rationale for immunotherapeutic combinations in solid tumors. J Immunother Cancer. 2021;9(8):e003005.
   PubMed Web of Science ®Google Scholar
• Park H, Bendell JC, Messersmith WA, et al. Preliminary clinical and biologic results of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab, in advanced solid tumors (KEYNOTE A36). J Clin Oncol. 2021;39(15_suppl):2505. suppl abstr 2505.
   Web of Science ®Google Scholar
• Freed-Pastor WA, Lambert LJ, Ely ZA, et al. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell. 2021;39(10):1342–1360.e14.
   PubMed Web of Science ®Google Scholar
• Saung MT, Muth S, Ding D, et al. Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. J Immunother Cancer. 2018;6(1):118.
   PubMedGoogle Scholar
• Gunderson AJ, Kaneda MM, Tsujikawa T, et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 2016;6(3):270–285.
   PubMed Web of Science ®Google Scholar
• Tempero M, Oh DY, Tabernero J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021;32(5):600–608.
   PubMed Web of Science ®Google Scholar
• Overman M, Javle M, Davis RE, et al. Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. J Immunother Cancer. 2020;8. 10.1136/jitc-2020-000587.
   Web of Science ®Google Scholar
• Yang S, Liu Q, Liao Q. Tumor-associated macrophages in pancreatic ductal adenocarcinoma: origin, polarization, function, and reprogramming. Front Cell Dev Biol. 2021;8:1552.
   Web of Science ®Google Scholar
• Tseng D, Volkmer J-P, Willingham SB, et al. Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc Natl Acad Sci U S A. 2013;110(27):11103–11108.
   PubMed Web of Science ®Google Scholar
• Jiang Z, Sun H, Yu J, et al. Targeting CD47 for cancer immunotherapy. J Hematol Oncol. 2021;14(1):180.
   PubMed Web of Science ®Google Scholar