The dark side of immunotherapy: pancreatic cancer

Abstract

Since the journal Science deemed cancer immunotherapy as the “breakthrough of the year” in 2014, there has been an explosion of clinical trials involving immunotherapeutic approaches that, in the last decade - thanks also to the renaissance of the immunosurveillance theory (renamed the three Es theory) - have been continuously and successfully developed. In the latest update of the development of the immuno-oncology drug pipeline, published last November by Nature Review Drug Discovery, it was clearly reported that the immunoactive drugs under study almost doubled in just two years. Of the different classes of passive and active immunotherapies, “cell therapy” is the fastest growing. The aim of this review is to discuss the preclinical and clinical studies that have focused on different immuno-oncology approaches applied to pancreatic cancer, which we assign to the “dark side” of immunotherapy, in the sense that it represents one of the solid tumors showing less response to this type of therapeutic strategy.

Keywords

Pancreatic cancer / immunotherapy / cancer vaccine / immune checkpoint / adoptive cell transfer

References

[1] Siegel RL,Jemal A.Cancer statistics, 2019..CA Cancer J Clin2019;69:7-34

[2] Siegel RL,Jemal A.Cancer statistics, 2020..CA Cancer J Clin2020;70:7-30

[3] Rahib L,Aizenberg R,Fleshman JM.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States..Cancer Res2014;74:2913-21

[4] Ren B,Suriawinata AA.Pancreatic ductal adenocarcinoma and its precursor lesions..Am J Pathol2019;189:9-21

[5] Hingorani SR,Maitra A,King C.Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse..Cancer Cell2003;4:437-50

[6] Weniger M,Liss AS.The extracellular matrix and pancreatic cancer: a complex relationship..Cancers (Basel)2018;10:316 PMCID:PMC6162452

[7] Adamska A,Falasca M.Pancreatic ductal adenocarcinoma: current and evolving therapies..IJMS2017;18:1338 PMCID:PMC5535831

[8] Chen DS.Oncology meets immunology: the cancer-immunity cycle..Immunity2013;39:1-10

[9] Soares KC,Edil B.Vaccines for pancreatic cancer..Cancer J2012;18:642-52 PMCID:PMC3539747

[10] Laheru D.Immunotherapy for pancreatic cancer - science driving clinical progress..Nat Rev Cancer2005;5:459-67

[11] Tomaino B,Capello M,Ponzetto A.Autoantibody signature in human ductal pancreatic adenocarcinoma..J Proteome Res2007;6:4025-31

[12] Cappello P,Chiarle R,Novarino A.An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen..Int J Cancer2009;125:639-48

[13] Cappello P,Novelli F.Pancreatic cancer vaccine: a unique potential therapy..Gastrointestinal Cancer Targets Ther2016;6:1-11

[14] Tomaino B,Capello M,Sperduti I.Circulating autoantibodies to phosphorylated α-enolase are a hallmark of pancreatic cancer..J Proteome Res2011;10:105-12

[15] Pandey R,Islam S,Barker NK.Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6 ) in Pancreatic Ductal Adenocarcinoma (PDA): an integrative analysis of a novel therapeutic target..Sci Rep2019;9:1-14 PMCID:PMC6893022

[16] Gautam SK,Dam V,Jain M.MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy..Semin Immunol2020;47:101391 PMCID:PMC7160012

[17] Dranoff G,Lazenby A,Levitsky H.Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity..Proc Natl Acad Sci USA1993;90:3539-43 PMCID:PMC46336

[18] Jaffee EM,Biedrzycki B,Schepers K.Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation..J Clin Oncol2001;19:145-56

[19] Lutz E,Lillemoe KD,Kobrin B.A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation..Ann Surg2011;253:328-35 PMCID:PMC3085934

[20] Laheru D,Burke J,Solt S.Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation..Clin Cancer Res2008;14:1455-63 PMCID:PMC2879140

[21] Lutz ER,Bigelow E,Mo G.Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation..Cancer Immunol Res2014;2:616-31 PMCID:PMC4082460

[22] Brockstedt DG,Leong ML,Gao Y.Listeria-based cancer vaccines that segregate immunogenicity from toxicity..Proc Natl Acad Sci USA2004;101:13832-7 PMCID:PMC518841

[23] Le DT,Nir-Paz R,Mathur S.A live-attenuated listeria vaccine (ANZ-100) and a live-attenuated listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase i studies of safety and immune induction..Clin Cancer Res2012;18:858-68 PMCID:PMC3289408

[24] Le DT,Picozzi V,Crocenzi T.Safety and survival with GVAX pancreas prime and listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer..J Clin Oncol2015;33:1325-33 PMCID:PMC4397277

[25] Le DT,Ko AH,Kindler H.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 Res2019;25:5493-502

[26] Gjertsen MK,Saeterdal I,Gaudernack G.Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation..Lancet1995;346:1399-400

[27] Gjertsen MK,Breivik J,Gedde-Dahl T.Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study..Int J Cancer1996;65:450-3

[28] Gjertsen MK,Rosseland AR,Gladhaug I.Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: clinical and immunological responses in patients with pancreatic adenocarcinoma..Int J Cancer2001;92:441-50

[29] Wedén S,Gladhaug IP,Eriksen JA.Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras..Int J Cancer2011;128:1120-8

[30] Bernhardt SL,Trachsel S,Eriksen JA.Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study..Br J Cancer2006;95:1474-82 PMCID:PMC2360729

[31] Shaw VE,Costello E,Park BK.Current status of GV1001 and other telomerase vaccination strategies in the treatment of cancer..Expert Rev Vaccines2010;9:1007-16

[32] Middleton G,Cox T,Wadsley J.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 Oncol2014;15:829-40

[33] Middleton G,Costello E,Cox T.Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma..Br J Cancer2016;114:510-8 PMCID:PMC4782200

[34] Neoptolemos JP,Cox TF,Shaw V.Predictive cytokine biomarkers for survival in patients with advanced pancreatic cancer randomized to sequential chemoimmunotherapy comprising gemcitabine and capecitabine (GemCap) followed by the telomerase vaccine GV1001 compared to concurrent chemoimmunotherapy in the TeloVac phase III trial..JCO2014;32:4121

[35] Kameshima H,Kutomi G,Iwayama Y.Immunotherapeutic benefit of α-interferon (IFN-α) in survivin2B-derived peptide vaccination for advanced pancreatic cancer patients..Cancer Sci2013;104:124-9

[36] Shima H,Wada S,Yasui H.Randomized phase II trial of survivin 2B peptide vaccination for patients with HLA-A24-positive pancreatic adenocarcinoma..Cancer Sci2019;110:2378-85 PMCID:PMC6676125

[37] Kubo T,Hirohashi Y,Ota Y.Immunohistological analysis of pancreatic carcinoma after vaccination with survivin 2B peptide: Analysis of an autopsy series..Cancer Sci2019;110:2386-95 PMCID:PMC6676134

[38] Osborne N,Burks J,Liu X.Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment..Cancer Immunol Immunother2019;68:1635-48 PMCID:PMC6814262

[39] Kajihara M,Kanai T,Matsumoto Y.Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer..World J Gastroenterol2016;22:4446-58 PMCID:PMC4858628

[40] Mukherjee P,Madsen CS,Adriance MC.Mice with spontaneous pancreatic cancer naturally develop MUC-1-specific CTLs that eradicate tumors when adoptively transferred..J Immunol2000;165:3451-60

[41] Lepisto AJ,Zeh H,Bartlett D.A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors..Cancer Ther2008;6:955-64 PMCID:PMC2614325

[42] Rong Y,Jin D,Wu L.A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer..Clin Exp Med2012;12:173-80

[43] Kobayashi M,Nagai K,Takahashi H.Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis..Cancer Immunol Immunother2014;63:797-806

[44] Mayanagi S,Sakurai T,Fujita T.Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer..Cancer Sci2015;106:397-406 PMCID:PMC4409883

[45] Koido S,Okamoto M,Mori M.Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms’ tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer..Clin Cancer Res2014;20:4228-39

[46] Takakura K,Kan S,Mori M.Prognostic markers for patient outcome following vaccination with multiple MHC class I/II-restricted WT1 peptide-pulsed dendritic cells plus chemotherapy for pancreatic cancer..Anticancer Res2015;35:555-62

[47] Mehrotra S,Chin S,Cloud CA.Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer..J Hematol Oncol2017;10:82 PMCID:PMC5384142

[48] Hobernik D.DNA vaccines - how far from clinical use?.International J Mol Sci2018;19:3605 PMCID:PMC6274812

[49] Raz E,Parker SE,Abai AM.Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses..PNAS1994;91:9519-23 PMCID:PMC44844

[50] Wolff JA,Williams P,Acsadi G.Direct gene transfer into mouse muscle in vivo..Science1990;247:1465-8

[51] Wang Z,Wang X,Pacchione SJ.Detection of integration of plasmid DNA into host genomic DNA following intramuscular injection and electroporation..Gene Ther2004;11:711-21

[52] Cappello P,Mandili G,Bulfamante S.Next generation immunotherapy for pancreatic cancer: DNA vaccination is seeking new combo partners..Cancers2018;10:51 PMCID:PMC5836083

[53] Capello M,Cappello P.α-enolase: a promising therapeutic and diagnostic tumor target..FEBS J2011;278:1064-74

[54] Cappello P,Bulfamante S.Alpha-Enolase (ENO1), a potential target in novel immunotherapies..Front Biosci (Landmark Ed)2017;22:944-59

[55] Cappello P,Chiarle R,Cavallo F.Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer..Gastroenterology2013;144:1098-106

[56] Pan RY,Chu MT,Chen HC.Recent development and clinical application of cancer vaccine: targeting neoantigens..J Immunol Res2018;2018:1-9 PMCID:PMC6313977

[57] Chen F,Du J,Shao J.Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors..J Clin Invest2019;129:2056-70 PMCID:PMC6486339

[58] Batista I.Exosomes and the future of immunotherapy in pancreatic cancer..IJMS2019;20:567 PMCID:PMC6387297

[59] Xiao L,Zhao K,Zöller M.Efficacy of vaccination with tumor-exosome loaded dendritic cells combined with cytotoxic drug treatment in pancreatic cancer..Oncoimmunology2017;6:e1319044 PMCID:PMC5486185

[60] Lu S,Du P,Yan W.A virus-infected, reprogrammed somatic cell-derived tumor cell (VIReST) vaccination regime can prevent initiation and progression of pancreatic cancer..Clin Cancer Res2020;26:465-76

[61] Met Ö,Chamberlain CA,Svane IM.Principles of adoptive T cell therapy in cancer..Semin Immunopathol2019;41:49-58

[62] Visioni A.Technical considerations for the generation of adoptively transferred T cells in cancer immunotherapy..Cancers (Basel)2016;8:86 PMCID:PMC5040988

[63] Wickström S.Expansion of tumor-infiltrating lymphocytes from melanoma tumors..Methods Mol Biol2019;1913:105-18

[64] Meng Q,Rangelova E,Ambati A.Expansion of tumor-reactive T cells from patients with pancreatic cancer..J Immunother2016;39:81-9

[65] Riddell SR,Berger C,Balakrishnan A.Adoptive therapy with chimeric antigen receptor-modified T cells of defined subset composition..Cancer J2014;20:141-4 PMCID:PMC4149222

[66] Wang LX,Disis ML.Adoptive transfer of tumor-primed, in vitro-activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response..Blood2007;109:4865-76 PMCID:PMC1885514

[67] Moeller M,Kershaw MH,Teng MWL.Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection..Blood2005;106:2995-3003

[68] Kennedy R.T helper lymphocytes rescue CTL from activation-induced cell death..J Immunol2006;177:2862-72 PMCID:PMC1594817

[69] Crompton JG,Restifo NP.Uncoupling T-cell expansion from effector differentiation in cell-based immunotherapy..Immunol Rev2014;257:264-76 PMCID:PMC3915736

[70] Gattinoni L,Ji Y,Paulos CM.A human memory T-cell subset with stem cell-like properties..Nat Med2011;17:1290-7 PMCID:PMC3192229

[71] Hall M,Malafa M,Hodul PJ.Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors..J Immunother Cancer2016;4:61 PMCID:PMC5067894

[72] McCarty TM,Sun JY,Diamond DJ.Targeting p53 for adoptive T-cell immunotherapy..Cancer Res1998;58:2601-5

[73] Zhou JH,Chen Q,Pei F.Relationship between telomerase activity and its subunit expression and inhibitory effect of antisense hTR on pancreatic carcinoma..World J Gastroenterol2003;9:1808-14 PMCID:PMC4611549

[74] Hassanin H,Schmidt J.Ex vivo expanded telomerase-specific T cells are effective in an orthotopic mouse model for pancreatic adenocarcinoma..Clin Exp Immunol2009;158:125-32 PMCID:PMC2759067

[75] Matsui H,Sakamoto K,Kanekiyo S.Postoperative adjuvant therapy for resectable pancreatic cancer with gemcitabine and adoptive immunotherapy..Pancreas2017;46:994-1002 PMCID:PMC5555975

[76] Kawaoka T,Takashima M,Yamamoto K.Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1..Oncol Rep2008;20:155-63

[77] Chung MJ,Bang S,Song SY.Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer..Cancer Immunol Immunother2014;63:939-46

[78] Wang M,Qi J,Tian J.S-1 plus CIK as second-line treatment for advanced pancreatic cancer..Med Oncol2013;30:747

[79] D’Ippolito E,Nauerth M.T cell engineering for adoptive T cell therapy: safety and receptor avidity..Cancer Immunol Immunother2019;68:1701-12

[80] Besser MJ,Itzhaki O,Zippel DB.Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies..Clin Cancer Res2013;19:4792-800

[81] Pilon-Thomas S,Ellwanger S,Royster E.Brief communication: efficacy of adoptive cell transfer of tumor infiltrating lymphocytes after lymphopenia induction for metastatic melanoma..J Immunother2012;35:615-20 PMCID:PMC4467830

[82] Rosenberg SA,Sherry RM,Hughes MS.Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy..Clin Cancer Res2011;17:4550-7 PMCID:PMC3131487

[83] Lauss M,Harbst K,Mitra S.Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma..Nat Commun2017;8:1-11 PMCID:PMC5701046

[84] Martinez M.CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment..Front Immunol2019;10:128 PMCID:PMC6370640

[85] Dufait I,Lanna A,Laranga R.Retroviral and lentiviral vectors for the induction of immunological tolerance..Scientifica (Cairo)2012;2012: PMCID:PMC3605697

[86] Kebriaei P,Narayanavari SA,Ivics Z.Gene therapy with the sleeping beauty transposon system..Trends Genet2017;33:852-70

[87] da Cunha JPC,de Souza JE,Carvalho PM.Bioinformatics construction of the human cell surfaceome..Proc Natl Acad Sci U S A2009;106:16752-7 PMCID:PMC2757864

[88] Cohen CJ,Segal D.Generation of recombinant immunotoxins for specific targeting of tumor-related peptides presented by MHC molecules..Methods Mol Biol2003;207:269-82

[89] Chmielewski M,Abken H.Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma..Immunol Rev2014;257:83-90

[90] Jones BS,Goldman F.Improving the safety of cell therapy products by suicide gene transfer..Front Pharmacol2014;5:254 PMCID:PMC4245885

[91] FDA. Research C for BE and KYMRIAH (tisagenlecleucel). Available from: http://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel [Last accessed on 15 Apr 2020]

[92] FDA. Research C for BE and YESCARTA (axicabtagene ciloleucel). Available from: http://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel [Last accessed on 15 Apr 2020]

[93] European Medicines Agency. First two CAR-T cell medicines recommended for approval in the European Union. Available from: https://www.ema.europa.eu/en/news/first-two-car-t-cell-medicines-recommended-approval-european-union [Last accessed on 15 Apr 2020]

[94] Hanahan D.Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment..Cancer Cell2012;21:309-22

[95] Ligtenberg MA,Mukhopadhyay M,Lladser A.Coexpressed catalase protects chimeric antigen receptor–redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity..J Immunol2016;196:759-66 PMCID:PMC4705591

[96] Juillerat A,Filhol JM,Valton J.An oxygen sensitive self-decision making engineered CAR T-cell..Sci Rep2017;7:39833 PMCID:PMC5247770

[97] Suarez ER,Sun J,Freeman GJ.Chimeric antigen receptor T cells secreting anti-PD-L1 antibodies more effectively regress renal cell carcinoma in a humanized mouse model..Oncotarget2016;7:34341-55 PMCID:PMC5085160

[98] Rafiq S,Jackson HJ,van Leeuwen DG.Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo..Nat Biotechnol2018;36:847-56 PMCID:PMC6126939

[99] Brentjens RJ,Park JH,Wang X.Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias..Blood2011;118:4817-28 PMCID:PMC3208293

[100] Dudley ME,Robbins PF,Hwu P.Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes..Science2002;298:850-4 PMCID:PMC1764179

[101] DeSelm CJ,Varghese AM.CAR T-cell therapy for pancreatic cancer..J Surg Oncol2017;116:63-74 PMCID:PMC5491361

[102] Pastan I.Discovery of mesothelin and exploiting it as a target for immunotherapy..Cancer Res2014;74:2907-12 PMCID:PMC4062095

[103] Shimizu A,Tani M,Okada KI.Coexpression of MUC16 and mesothelin is related to the invasion process in pancreatic ductal adenocarcinoma..Cancer Sci2012;103:739-46

[104] Servais EL,Rodriguez L,Nitadori J.Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients..Clin Cancer Res2012;18:2478-89 PMCID:PMC3759995

[105] Bharadwaj U,Li M,Yao Q.Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression..Mol Cancer2011;10:106 PMCID:PMC3175472

[106] Chen SH,Wang P,Konstantopoulos K.Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation..Sci Rep2013;3:1870 PMCID:PMC3660778

[107] Morello A,Adusumilli PS.Mesothelin-targeted CARs: driving T cells to solid tumors..Cancer Discov2016;6:133-46 PMCID:PMC4744527

[108] Stromnes IM,Hulbert A,Nguyen H.T cells engineered against a native antigen can surmount immunologic and physical barriers to treat pancreatic ductal adenocarcinoma..Cancer Cell2015;28:638-52 PMCID:PMC4724422

[109] Beatty GL,Lacey SF,Nazimuddin F.Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial..Gastroenterology2018;155:29-32 PMCID:PMC6035088

[110] Morrison AH,Vonderheide RH.Immunotherapy and prevention of pancreatic cancer..Trends Cancer2018;4:418-28 PMCID:PMC6028935

[111] Burtness B.Her signaling in pancreatic cancer..Expert Opin Biol Ther2007;7:823-9

[112] Ishiwata T,Yoshimura H,Ishiwata S.Pancreatic cancer stem cells: features and detection methods..Pathol Oncol Res2018;24:797-805

[113] Maliar A,Waks T,Lavy R.Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice..Gastroenterology2012;143:1375-84.e5

[114] Morgan RA,Kitano M,Laurencot CM.Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2..Mol Ther2010;18:843-51 PMCID:PMC2862534

[115] Raj D,Rodgers D,Begum J.Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma..Gut2019;68:1052-64 PMCID:PMC6580747

[116] Gold P.Specific carcinoembryonic antigens of the human digestive system..J Exp Med1965;122:467-81 PMCID:PMC2138078

[117] Hammarström S.The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues..Semin Cancer Biol1999;9:67-81

[118] Chmielewski M,Rappl G,Schmidt-Wolf IH.T cells that target carcinoembryonic antigen eradicate orthotopic pancreatic carcinomas without inducing autoimmune colitis in mice..Gastroenterology2012;143:1095-107.e2

[119] Parkhurst MR,Langan RC,Nathan DAN.T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis..Mol Ther2011;19:620-6 PMCID:PMC3048186

[120] Jewett A,Fong Y,Safaei T.NK cells shape pancreatic and oral tumor microenvironments; role in inhibition of tumor growth and metastasis..Semin Cancer Biol2018;53:178-88

[121] Chi X,Zhang E,Xu H.Significantly increased anti-tumor activity of carcinoembryonic antigen-specific chimeric antigen receptor T cells in combination with recombinant human IL-12..Cancer Med2019;8:4753-65 PMCID:PMC6712469

[122] Chmielewski M.CAR T cells releasing IL-18 convert to T-bethigh FoxO1low effectors that exhibit augmented activity against advanced solid tumors..Cell Rep2017;21:3205-19

[123] Zhang E,Gu J,Chi X.Recombination of a dual-CAR-modified T lymphocyte to accurately eliminate pancreatic malignancy..J Hematol Oncol2018;11:102 PMCID:PMC6090669

[124] Taylor-Papadimitriou J,Graham R.Latest developments in MUC1 immunotherapy..Biochem Soc Trans2018;46:659-68 PMCID:PMC6008591

[125] Posey AD,Boesteanu AC,Mandel U.Engineered CAR T cells targeting the cancer-associated Tn-Glycoform of the membrane mucin MUC1 control adenocarcinoma..Immunity2016;44:1444-54 PMCID:PMC5358667

[126] Levi E,Adsay NV,Basturk O.MUC1 and MUC2 in pancreatic neoplasia..J Clin Pathol2004;57:456-62 PMCID:PMC1770304

[127] Yazdanifar M,Grover P,Bose M.Overcoming immunological resistance enhances the efficacy of a novel anti-tMUC1-CAR T cell treatment against pancreatic ductal adenocarcinoma..Cells2019;8:1070 PMCID:PMC6770201

[128] Abate-Daga D,Tran E,Gattinoni L.A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer..Hum Gene Ther2014;25:1003-12 PMCID:PMC4270113

[129] Mohammed S,Bajgain P,Heslop HE.Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer..Mol Ther2017;25:249-58 PMCID:PMC5363304

[130] Golubovskaya V,Zhou H,Harto H.CD47-CAR-T cells effectively kill target cancer cells and block pancreatic tumor growth..Cancers (Basel)2017;9:139 PMCID:PMC5664078

[131] Du H,Ahn S,Montgomery SA.Antitumor responses in the absence of toxicity in solid tumors by targeting B7-H3 via chimeric antigen receptor T cells..Cancer Cell2019;35:221-37.e8 PMCID:PMC6645919

[132] Whilding LM,Zabinski T,Petrovic RMG.Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T cells..Mol Ther2017;25:259-73 PMCID:PMC5261028

[133] Masu T,Nakatsuka K,Miura D.Anti-CD137 monoclonal antibody enhances trastuzumab-induced, natural killer cell-mediated cytotoxicity against pancreatic cancer cell lines with low human epidermal growth factor-like receptor 2 expression..PLoS One2018;13:e0200664 PMCID:PMC6312288

[134] Springfeld C,Büchler MW,Hackert T.Chemotherapy for pancreatic cancer..Presse Med2019;48:e159-74

[135] Posner MR,Upton MP,Gornstein ER.Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines..Clin Cancer Res1999;5:2261-70

[136] Hess S.A novel function of CD40: induction of cell death in transformed cells..J Exp Med1996;183:159-67 PMCID:PMC2192400

[137] Weiss JM,Quiñones OA,Wiltrout RH.CD40 expression in renal cell carcinoma is associated with tumor apoptosis, CD8(+) T cell frequency and patient survival..Hum Immunol2014;75:614-20 PMCID:PMC6266867

[138] Beatty GL,Fishman MP,Teitelbaum UR.CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans..Science2011;331:1612-6 PMCID:PMC3406187

[139] French RR,Tutt AL.CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help..Nat Med1999;5:548-53

[140] Sotomayor EM,Tubb E,Bien H.Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40..Nat Med1999;5:780-7

[141] Beatty GL,Long KB.Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists..Expert Rev Anticancer Ther2017;17:175-86 PMCID:PMC5533512

[142] Ahonen CL,McGurran SM,Wade WF.Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN..J Exp Med2004;199:775-84 PMCID:PMC2212721

[143] Murphy WJ,Back T,Subleski J.Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses..J Immunol2003;170:2727-33

[144] Buhtoiarov IN,Berke G,Sondel PM.CD40 ligation activates murine macrophages via an IFN-gamma-dependent mechanism resulting in tumor cell destruction in vitro..J Immunol2005;174:6013-22

[145] Banchereau J,Valle A,Rousset F.Long-term human B cell lines dependent on interleukin-4 and antibody to CD40..Science1991;251:70-2

[146] Schultze JL,Seamon MJ,Jung K.CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy..J Clin Invest1997;100:2757-65 PMCID:PMC508480

[147] Mathieu M,Daudelin JF,Lapointe R.CD40-activated B cells can efficiently prime antigen-specific naïve CD8+ T cells to generate effector but not memory T cells..Plos One2012;7:e30139 PMCID:PMC3264565

[148] Hunter TB,Gladue RP,Antonia SJ.An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model..Scand J Immunol2007;65:479-86

[149] Winograd R,Evans RA,Meyer ARL.Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma..Cancer Immunol Res2015;3:399-411 PMCID:PMC4390506

[150] Heath WR.Cross-presentation, dendritic cells, tolerance and immunity..Annu Rev Immunol2001;19:47-64

[151] Nowak AK,Lake RA.Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors..Cancer Res2003;63:4490-6

[152] Byrne KT.CD40 stimulation obviates innate sensors and drives T cell immunity in cancer..Cell Rep2016;15:2719-32 PMCID:PMC4917417

[153] Beatty GL,Evans RA,Luque SL.Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages..Gastroenterology2015;149:201-10 PMCID:PMC4478138

[154] Vonderheide RH,Winograd R,Bayne LJ.CD40 immunotherapy for pancreatic cancer..Cancer Immunol Immunother2013;62:949-54 PMCID:PMC3731141

[155] Beatty GL,Chiorean EG,Brothers A.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 Res2013;19:6286-95 PMCID:PMC3834036

[156] Stromnes IM,Izeradjene K,Cuevas C.Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity..Gut2014;63:1769-81 PMCID:PMC4340484

[157] Quaranta V.Macrophage-mediated subversion of anti-tumour immunity..Cells2019;8:747 PMCID:PMC6678757

[158] Lenzo JC,Cook AD,Anderson GP.Control of macrophage lineage populations by CSF-1 receptor and GM-CSF in homeostasis and inflammation..Immunol Cell Biol2012;90:429-40

[159] Ries CH,Hoves S,Wartha K.Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy..Cancer Cell2014;25:846-59

[160] Quaranta V,Nielsen SR,Ahmed MS.Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer..Cancer Res2018;78:4253-69 PMCID:PMC6076440

[161] Zhu Y,Meyer MA,West BL.CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models..Cancer Res2014;74:5057-69 PMCID:PMC4182950

[162] Mitchem JB,Knolhoff BL,Zhu Y.Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses..Cancer Res2013;73:1128-41 PMCID:PMC3563931

[163] Zheng Y,Liu M,Mead KI.CD86 and CD80 Differentially modulate the suppressive function of human regulatory T Cells..J Immunol2004;172:2778-84

[164] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy..Nat Rev Cancer2012;12:252-64 PMCID:PMC4856023

[165] Sharpe AH,Ahmed R.The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection..Nat Immunol2007;8:239-45

[166] Melero I,Aznar MA,Gracia JLP.Evolving synergistic combinations of targeted immunotherapies to combat cancer..Nat Rev Cancer2015;15:457-72

[167] Zou W.Inhibitory B7-family molecules in the tumour microenvironment..Nat Rev Immunol2008;8:467-77

[168] Binnewies M,Kersten K,Fearon DF.Understanding the tumor immune microenvironment (TIME) for effective therapy..Nat Med2018;24:541-50 PMCID:PMC5998822

[169] Clark CE,Mick R,Tuveson DA.Dynamics of the immune reaction to pancreatic cancer from inception to invasion..Cancer Res2007;67:9518-27

[170] Ino Y,Shimada K,Kosuge T.Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer..Br J Cancer2013;108:914-23 PMCID:PMC3590668

[171] Amedei A,Benagiano M,Cianchi F.Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions..Cancer Immunol Immunother2013;62:1249-60

[172] Fukunaga A,Cho Y,Kawarada Y.CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma..Pancreas2004;28:e26-31

[173] Birnbaum DJ,Lopresti A,Poizat F.Prognostic value of PDL1 expression in pancreatic cancer..Oncotarget2016;7:71198-210 PMCID:PMC5342072

[174] Rahn S,Mennrich R,Wesch D.POLE Score: a comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma..Oncotarget2019;10:1572-88 PMCID:PMC6422186

[175] Hodi FS,McDermott DF,Sosman JA.Improved survival with ipilimumab in patients with metastatic melanoma..N Engl J Med2010;363:711-23 PMCID:PMC3549297

[176] Bengsch F,Liu A,Beatty GL.CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer..Cancer Immunol Immunother2017;66:1609-17 PMCID:PMC5677559

[177] Royal RE,Turner K,Hughes M.Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma..J Immunother2010;33:828-33

[178] Looi CK,Leong CO,Rosli R.Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment..J Exp Clin Cancer Res2019;38:162 PMCID:PMC6463646

[179] Nomi T,Akahori T,Kubo A.Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer..Clin Cancer Res2007;13:2151-7

[180] Brahmer JR,Chow LQM,Topalian SL.Safety and activity of anti–PD-L1 antibody in patients with advanced cancer..N Engl J Med2012;366:2455-65 PMCID:PMC3563263

[181] Le DT,Smith KN,Bartlett BR.Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade..Science2017;357:409-13 PMCID:PMC5576142

[182] Humphris JL,Nones K,Johns AL.Hypermutation in pancreatic cancer..Gastroenterology2017;152:68-74.e2

[183] Beatty GL.Immune escape mechanisms as a guide for cancer immunotherapy..Clin Cancer Res2015;21:687-92 PMCID:PMC4334715

[184] Kabacaoglu D,Ruess DA.Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: current limitations and future options..Front Immunol2018;9:1878 PMCID:PMC6104627

[185] Brown JS,Lopez J.Combining DNA damaging therapeutics with immunotherapy: more haste, less speed..Br J Cancer2018;118:312-24 PMCID:PMC5808021

[186] Henriksen A,Chen I.Checkpoint inhibitors in pancreatic cancer..Cancer Treat Rev2019;78:17-30

[187] Aglietta M,Sawyer MB,Miller WH.A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer..Ann Oncol2014;25:1750-5

[188] Kamath SD,Kircher S,Fought AJ.Ipilimumab and gemcitabine for advanced pancreatic cancer: a phase Ib study..Oncologist2019;

[189] Weiss GJ,Beck J,Urnovitz H.Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma..Invest New Drugs2018;36:96-102

[190] Wainberg ZA,Kim EJH,Kalyan A.Phase I study of nivolumab (Nivo) + nab-paclitaxel (nab-P) + gemcitabine (Gem) in advanced pancreatic cancer (APC)..JCO2019;37:298

[191] Burnette B.Radiation as an immune modulator..Semin Radiat Oncol2013;23:273-80

[192] Demaria S,Formenti SC.Radiotherapy: changing the game in immunotherapy..Trends Cancer2016;2:286-94 PMCID:PMC5070800

[193] Weichselbaum RR,Deng L.Radiotherapy and immunotherapy: a beneficial liaison?.Nat Rev Clin Oncol2017;14:365-79

[194] Azad A,D’Costa Z,Diana A.PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy..EMBO Mol Med2017;9:167-80 PMCID:PMC5286375

[195] Victor CTS,Maity A,Pauken KE.Radiation and dual checkpoint blockade activates non-redundant immune mechanisms in cancer..Nature2015;520:373-7 PMCID:PMC4401634

[196] Rech AJ,Kotzin JJ,Minn AJ.Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer..Cancer Res2018;78:4282-91 PMCID:PMC6415684

[197] Guo S,Miller G,Wu J.Immunotherapy in pancreatic cancer: unleash its potential through novel combinations..World J Clin Oncol2017;8:230-40 PMCID:PMC5465012

[198] Le DT,Uram JN,Onners B.Evaluation of Ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer..J Immunother2013;36:382-9 PMCID:PMC3779664

[199] Soares KC,Wu AA,Xiao Q.PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T cell infiltration into pancreatic tumors..J Immunother2015;38:1-11 PMCID:PMC4258151

[200] Lutz ER,Jaffee EM.Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy..Oncoimmunology2014;3e962401 PMCID:PMC4292514

[201] Hilmi M,Neuzillet C.Immune therapies in pancreatic ductal adenocarcinoma: where are we now?.World J Gastroenterol2018;24:2137-51 PMCID:PMC5974576

[202] Griffith KD,Carrasquillo JA,Yang JC.In vivo distribution of adoptively transferred indium-111-labeled tumor infiltrating lymphocytes and peripheral blood lymphocytes in patients with metastatic melanoma..J Natl Cancer Inst1989;81:1709-17

[203] Bourquin C,Zoglmeier C,Sandholzer N.Efficient eradication of subcutaneous but not of autochthonous gastric tumors by adoptive T cell transfer in an SV40 T antigen mouse model..J Immunol2010;185:2580-8

[204] Abate-Daga D,Davis JL,Rosenberg SA.Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes..Blood2013;122:1399-410 PMCID:PMC3750338

[205] Daud AI,Robert C,Weber JS.Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma..J Clin Oncol2016;34:4102-9 PMCID:PMC5562434

[206] Iafolla MAJ.Update on programmed death-1 and programmed death-ligand 1 inhibition in the treatment of advanced or metastatic non-small cell lung cancer..Front Oncol2017;7:67 PMCID:PMC5382272

[207] Rataj F,Chaloupka M,Heise C.PD1-CD28 fusion protein enables CD4+ T cell help for adoptive T cell therapy in models of pancreatic cancer and non-hodgkin lymphoma..Front Immunol2018;9:1955 PMCID:PMC6125378

[208] John LB,Duong CPM,Beavis PA.Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells..Clin Cancer Res2013;19:5636-46

[209] Blair AB.Rational combinations of immunotherapy for pancreatic ductal adenocarcinoma..Chin Clin Oncol2017;6:31 PMCID:PMC6178804

[210] Hu B,Zhang L,Niedermann G.Nucleofection with plasmid DNA for CRISPR/Cas9-mediated inactivation of programmed cell death protein 1 in CD133-specific CAR T cells..Human Gene Therapy2018;30:446-58

[211] Candido JB,Bailey P,Karim SA.CSF1R+ macrophages sustain pancreatic tumor growth through T cell suppression and maintenance of key gene programs that define the squamous subtype..Cell Rep2018;23:1448-60 PMCID:PMC5946718

[212] Kumar V,Tcyganov E.The nature of myeloid-derived suppressor cells in the tumor microenvironment..Trends Immunol2016;37:208-20 PMCID:PMC4775398 [Available on 2017-03-01]

[213] Bastid J,Alberici G,Eliaou JF.ENTPD1/CD39 is a promising therapeutic target in oncology..Oncogene2013;32:1743-51

[214] Deaglio S,Gao W,Usheva A.Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression..J Exp Med2007;204:1257-65 PMCID:PMC2118603

[215] Ohue Y.Regulatory T (Treg) cells in cancer: can treg cells be a new therapeutic target?.Cancer Sci2019;110:2080-9 PMCID:PMC6609813

[216] Pandha H,John J.Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines..Clin Exp Immunol2007;148:127-35 PMCID:PMC1868855

[217] Bharadwaj U,Zhang R,Yao Q.Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation..Cancer Res2007;67:5479-88

[218] Fogar P,Fadi E,Pantano G.Pancreatic cancer alters human CD4+ T lymphocyte function: a piece in the immune evasion puzzle..Pancreas2011;40:1131-7

[219] Sharma P,Wolchok JD.Novel cancer immunotherapy agents with survival benefit: recent successes and next steps..Nat Rev Cancer2011;11:805-12 PMCID:PMC3426440

[220] Bailey P,Nones K,Patch AM.Genomic analyses identify molecular subtypes of pancreatic cancer..Nature2016;531:47-52

[221] Maleki Vareki S.High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors..J Immunother Cancer2018;6:157 PMCID:PMC6307306