Recent advances in immunotherapy for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a disease with a dismal prognosis. Since 1996 there have only been two upfront regimens found to be superior to gemcitabine: FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin), and gemcitabine plus nab-paclitaxel. Despite the improvement noted in these trials, PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance. The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments. Therapeutic vaccines, combination treatments, adoptive T cell transfer, as well as immunomodulators are being explored. With the emerging use of immunotherapy and immunomodulators, the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC. Overall, results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.

Keywords

Pancreatic ductal adenocarcinoma / chemoresistance / desmoplasia / tumor microenvironment / extracellular matrix / immunogenicity / immunotherapy / vaccines / immune checkpoint inhibitors / immunomodulation

References

[1] American Cancer Society. Cancer Facts & Statistics. Available from: http://cancerstatisticscenter.cancer.org/. [Last accessed on 30 Oct 2020]

[2] 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

[3] SEER Cancer Statistics Review (CSR) 1975-2017. Available from: https://seer.cancer.gov/csr/1975_2017/index.html. [Last accessed on 30 Oct 2020]

[4] Burris HA,Andersen J.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial..J Clin Oncol1997;15:2403-13

[5] Philip PA,Corless CL.Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205..J Clin Oncol2010;28:3605-10 PMCID:PMC2917315

[6] Kindler HL,Hollis D.Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303)..J Clin Oncol2010;28:3617-22 PMCID:PMC2917317

[7] Louvet C,Hammel P.Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial..J Clin Oncol2005;23:3509-16

[8] Berlin JD,Thomas JP,Haller DG.Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297..J Clin Oncol2002;20:3270-5

[9] Herrmann R,Ruhstaller T.Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group..J Clin Oncol2007;25:2212-7

[10] Rocha Lima CM,Rotche R.Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate..J Clin Oncol2004;22:3776-83

[11] Conroy T,Ychou M.FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer..N Engl J Med2011;364:1817-25

[12] Von Hoff DD,Arena FP.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine..N Engl J Med2013;369:1691-703 PMCID:PMC4631139

[13] Neoptolemos JP,Ghaneh P.Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial..Lancet2017;389:1011-24

[14] Conroy T,Hebbar M.FOLFIRINOX or Gemcitabine as adjuvant therapy for pancreatic cancer..N Engl J Med2018;379:2395-406

[15] Chand S,Blanco FF,Brody JR.The landscape of pancreatic cancer therapeutic resistance mechanisms..Int J Biol Sci2016;12:273-82 PMCID:PMC4753156

[16] Nixon NA,Ernst S.Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges..Curr Oncol2018;25:e373-84 PMCID:PMC6209564

[17] Kessenbrock K,Werb Z.Matrix metalloproteinases: regulators of the tumor microenvironment..Cell2010;141:52-67 PMCID:PMC2862057

[18] Conway JR,Evans TJ,Timpson P.Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine..Gut2019;68:742-58 PMCID:PMC6580874

[19] Apte MV,Lugea A.A starring role for stellate cells in the pancreatic cancer microenvironment..Gastroenterology2013;144:1210-9 PMCID:PMC3729446

[20] Löhr M,Ringel J.Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma..Cancer Res2001;61:550-5

[21] Hessmann E,Klein L.Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer..Gut2018;67:497-507 PMCID:PMC5868285

[22] Hartmann N,Giese T.Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer..Clin Cancer Res2014;20:3422-33

[23] Armstrong T,Murphy LB.Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma..Clin Cancer Res2004;10:7427-37

[24] Provenzano PP,Chang AE,Von Hoff DD.Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma..Cancer Cell2012 20;21:418-29 PMCID:PMC3371414

[25] Jacobetz MA,Neesse A.Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer..Gut2013;62:112-20 PMCID:PMC3551211

[26] Erkan M,Kleeff J.The role of hypoxia in pancreatic cancer: a potential therapeutic target?.Expert Rev Gastroenterol Hepatol2016;10:301-16

[27] Halozyme Announces HALO-301 Phase 3 Study Fails To Meet Primary Endpoint. Available from: https://www.halozyme.com/investors/news-releases/news-release-details/2019/Halozyme-Announces-HALO-301-Phase-3-Study-Fails-To-Meet-Primary-Endpoint/default.aspx. [Last accessed on 30 Oct 2020]

[28] Öhlund D,Biffi G.Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer..J Exp Med2017;214:579-96 PMCID:PMC5339682

[29] Neesse A,Tuveson DA.Stromal biology and therapy in pancreatic cancer: a changing paradigm..Gut2015;64:1476-84

[30] Mace TA,Lesinski GB.Pancreatic cancer-associated stellate cells: a viable target for reducing immunosuppression in the tumor microenvironment..Oncoimmunology2013;2:e24891 PMCID:PMC3782129

[31] Nagathihalli NS,VanSaun MN.Pancreatic stellate cell secreted IL-6 stimulates STAT3 dependent invasiveness of pancreatic intraepithelial neoplasia and cancer cells..Oncotarget2016;7:65982-92 PMCID:PMC5323208

[32] Ugel S,Mandruzzato S.Tumor-induced myeloid deviation: when myeloid-derived suppressor cells meet tumor-associated macrophages..J Clin Invest2015;125:3365-76 PMCID:PMC4588310

[33] Schumacher TN.Neoantigens in cancer immunotherapy..Science2015;348:69-74

[34] Brown SD,Gibb EA.Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival..Genome Res2014;24:743-50 PMCID:PMC4009604

[35] Rooney MS,Wu CJ,Hacohen N.Molecular and genetic properties of tumors associated with local immune cytolytic activity..Cell2015;160:48-61 PMCID:PMC4856474

[36] Yarchoan M,Jaffee EM.Tumor mutational burden and response rate to PD-1 inhibition..N Engl J Med2017;377:2500-1 PMCID:PMC6549688

[37] Evans A.The role of inflammatory cells in fostering pancreatic cancer cell growth and invasion..Front Physiol2012;3:270 PMCID:PMC3431795

[38] Ryschich E,Hinz U.Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma..Clin Cancer Res2005;11:498-504

[39] Tewari N,Arora A,Ilyas M.The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays..BMC Cancer2013;13:436 PMCID:PMC3849604

[40] Rosenberg SA,Restifo NP.Cancer immunotherapy: moving beyond current vaccines..Nat Med2004;10:909-15 PMCID:PMC1435696

[41] Ito A,Tada K.Clinical development of immune checkpoint inhibitors..Biomed Res Int2015;2015:605478 PMCID:PMC4486755

[42] Brunet JF,Luciani MF.A new member of the immunoglobulin superfamily--CTLA-4..Nature1987;328:267-70

[43] Ishida Y,Shibahara K.Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death..EMBO J1992;11:3887-95 PMCID:PMC556898

[44] Taube JM,Brahmer JR.Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy..Clin Cancer Res2014;20:5064-74 PMCID:PMC4185001

[45] Royal RE,Turner K.Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma..J Immunother Hagerstown Md 19972010;33:828-33 PMCID:PMC7322622

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

[47] Patnaik A,Rasco D.Phase I study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in patients with advanced solid tumors..Clin Cancer Res2015;21:4286-93

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

[49] Hu ZI,Stadler ZK.Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations..Clin Cancer Res2018;24:1326-36 PMCID:PMC5856632

[50] Le DT,Wang H.PD-1 blockade in tumors with mismatch-repair deficiency..N Engl J Med2015;372:2509-20 PMCID:PMC4481136

[51] Chen M,Fan L.Combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with mismatch repair proficiency but high tumor mutation burden: a case report..Pancreas2019;48:1232-6 PMCID:PMC6830947

[52] Mohindra N,Nimeiri H.Results of the phase Ib study of ipilimumab and gemcitabine for advanced pancreas cancer..J Clin Oncol2015;33:e15281

[53] Kalyan A,Mohindra NA.Ipilimumab and gemcitabine for advanced pancreas cancer: a phase Ib study..J Clin Oncol2016;34:e15747

[54] O’Reilly EM,Dhani N.Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial..JAMA Oncol2019;5:1431-8 PMCID:PMC6647002

[55] Ng J.Radiation therapy and the abscopal effect: a concept comes of age..Ann Transl Med2016;4:118 PMCID:PMC4828732

[56] Park B,Lee KM.The effect of radiation on the immune response to cancers..Int J Mol Sci2014;15:927-43 PMCID:PMC3907847

[57] Tsuchikawa T,Tanaka E.Novel aspects of preoperative chemoradiation therapy improving anti-tumor immunity in pancreatic cancer..Cancer Sci2013;104:531-5

[58] Homma Y,Murakami T.Immunological impact of neoadjuvant chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma..Ann Surg Oncol2014;21:670-6

[59] Twyman-Saint Victor C,Maity A.Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer..Nature2015;520:373-7 PMCID:PMC4401634

[60] Seifert L,Tiwari S.Radiation therapy induces macrophages to suppress T-cell responses against pancreatic tumors in mice..Gastroenterology2016;150:1659-72.e5 PMCID:PMC4909514

[61] Katz MHG,Bauer TW.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 Oncol2017;35:4125

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

[63] Wu AA,Lee V.Current status of immunotherapies for treating pancreatic cancer..Curr Oncol Rep2019;21:60

[64] Ward JP,Schreiber RD.The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer..Adv Immunol2016;130:25-74 PMCID:PMC6087548

[65] Johnson BA,Lee V,Jaffee EM.Strategies for Increasing Pancreatic Tumor Immunogenicity..Clin Cancer Res2017;23:1656-69 PMCID:PMC5466881

[66] 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

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

[68] Jaffee EM,Biedrzycki B.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

[69] Lutz E,Lillemoe KD.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

[70] Le DT,Uram JN.Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer..J Immunother Hagerstown Md 19972013;36:382-9 PMCID:PMC3779664

[71] Inc LP. NewLink genetics announces results from phase 3 IMPRESS trial of Algenpantucel-L for patients with resected pancreatic cancer. GlobeNewswire News Room. 2016. Available from: http://www.globenewswire.com/news-release/2016/05/09/837878/0/en/NewLink-Genetics-Announces-Results-from-Phase-3-IMPRESS-Trial-of-Algenpantucel-L-for-Patients-with-Resected-Pancreatic-Cancer.html. [Last accessed on 30 Oct 2020]

[72] Lauer P,Loessner MJ,Calendar R.Construction, characterization, and use of two Listeria monocytogenes site-specific phage integration vectors..J Bacteriol2002;184:4177-86 PMCID:PMC135211

[73] Brockstedt DG,Leong ML.Listeria-based cancer vaccines that segregate immunogenicity from toxicity..Proc Natl Acad Sci U S A2004;101:13832-7 PMCID:PMC518841

[74] Le DT,Picozzi V.Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer..J Clin Oncol Off2015;33:1325-33 PMCID:PMC4397277

[75] Le DT,Ko AH.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 PMCID:PMC7376746

[76] A randomized, placebo-controlled, double blind, multicenter phase II adjuvant trial of the efficacy, immunogenicity, and safety of GI-4000 plus gem versus gem alone in patients with resected pancreas cancer with activating RAS mutations/survival and immunology analysis of the R1 subgroup. Available from: https://ascopubs.org/doi/abs/10.1200/jco.2012.30.15_suppl.e14501. [Last accessed on 30 Oct 2020]

[77] Finke LH,Blumenstein B,Levitsky H.Lessons from randomized phase III studies with active cancer immunotherapies - outcomes from the 2006 Meeting of the Cancer Vaccine Consortium (CVC)..Vaccine2007;25:B97-109

[78] Ott PA,Keskin DB.An immunogenic personal neoantigen vaccine for patients with melanoma..Nature2017;547:217-21 PMCID:PMC5577644

[79] Yamaue H,Tani M.Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC study..Cancer Sci2015;106:883-90 PMCID:PMC4520640

[80] Asahara S,Yamao K,Yamaue H.Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer..J Transl Med2013;11:291 PMCID:PMC4225607

[81] Gjertsen MK,Rosseland AR.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

[82] VXM01, an oral T-cell vaccine targeting the tumor vasculature: results from a randomized, controlled, first-in-man study in pancreatic cancer patients. Available from: https://meetinglibrary.asco.org/record/84680/abstract. [Last accessed on 30 Oct 2020]

[83] Kondo H,Kawaoka T.Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes..Anticancer Res2008;28:379-87

[84] Tanyi JL,Ophir E.Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer..Sci Transl Med2018;10:

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

[86] Lord CJ.BRCAness revisited..Nat Rev Cancer2016;16:110-20

[87] Golan T,Reni M.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer..N Engl J Med2019;381:317-27 PMCID:PMC6810605

[88] Kheder ES.Emerging targeted therapy for tumors with NTRK fusion proteins..Clin Cancer Res2018;24:5807-14

[89] Levy JMM,Thorburn A.Targeting autophagy in cancer..Nat Rev Cancer2017;17:528-42 PMCID:PMC5975367

[90] Sulzmaier FJ,Schlaepfer DD.FAK in cancer: mechanistic findings and clinical applications..Nat Rev Cancer2014;14:598-610 PMCID:PMC4365862

[91] Bennewith KL,Ham CM.The role of tumor cell-derived connective tissue growth factor (CTGF/CCN2) in pancreatic tumor growth..Cancer Res2009;69:775-84 PMCID:PMC2747032

[92] Neesse A,Bapiro TE.CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer..Proc Natl Acad Sci2013;110:12325-30 PMCID:PMC3725120

[93] Picozzi VJ,Mody K.Effect of anti-CTGF human recombinant monoclonal antibody pamrevlumab on resectability and resection rate when combined with gemcitabine/nab-paclitaxel in phase 1/2 clinical study for the treatment of locally advanced pancreatic cancer patients..J Clin Oncol2018;36:4016