1.
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.
PubMedCrossRef
2.
Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252–61.
PubMedCentralPubMedCrossRef
3.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.
PubMedCrossRef
4.
Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, Kanai Y, et al. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer. 2013;108(4):914–23.
PubMedCentralPubMedCrossRef
5.
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306.
PubMedCrossRef
6.
Collins MA, Bednar F, Zhang Y, Brisset JC, Galban S, Galban CJ, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–53.
PubMedCentralPubMedCrossRef
7.
Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012;18(16):4266–76.
PubMedCentralPubMedCrossRef
8.
Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, 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.
PubMedCrossRef
9.
Protti MP, De Monte L. Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol. 2013;4:210.
PubMedCentralPubMedCrossRef
10.
Davis M, Conlon K, Bohac GC, Barcenas J, Leslie W, Watkins L, et al. Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas. J Immunother. 2012;35(8):629–40.
PubMedCrossRef
11.
Duan X, Deng L, Chen X, Lu Y, Zhang Q, Zhang K, et al. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol. 2011;28(2):466–74.
PubMedCrossRef
12.
Sideras K, Braat H, Kwekkeboom J, van Eijck CH, Peppelenbosch MP, Sleijfer S, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat Rev. 2014;40(4):513–22.
PubMedCrossRef
13.
Wachsmann MB, Pop LM, Vitetta ES. Pancreatic ductal adenocarcinoma: a review of immunologic aspects. J Investig Med. 2012;60(4):643–63.
PubMedCentralPubMed
15.
Vonderheide RH, Bayne LJ. Inflammatory networks and immune surveillance of pancreatic carcinoma. Curr Opin Immunol. 2013;25(2):200–5.
PubMedCentralPubMedCrossRef
16.
Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011;60(10):1419–30.
PubMedCentralPubMedCrossRef
17.
Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Yamao J, Kim S, et al. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res. 2012;173(2):299–308.
PubMedCrossRef
18.
Tjomsland V, Spangeus A, Sandstrom P, Borch K, Messmer D, Larsson M. Semi mature blood dendritic cells exist in patients with ductal pancreatic adenocarcinoma owing to inflammatory factors released from the tumor. PLoS One. 2010;5(10):e13441.
PubMedCentralPubMedCrossRef
19.
Unek T, Unek IT, Agalar AA, Sagol O, Ellidokuz H, Ertener O, et al. CD40 expression in pancreatic cancer. Hepatogastroenterology. 2013;60(128):2085–93.
PubMed
20.
Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol. 2013;25(2):230–7.
PubMedCrossRef
21.
Cheuk AT, Mufti GJ, Guinn BA. Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer Gene Ther. 2004;11(3):215–26.
PubMedCrossRef
22.
Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, et al. Clinical roles of increased populations of Foxp3 + CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas. 2006;33(4):386–90.
PubMedCrossRef
23.
Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S, et al. Circulating CD4 + CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas. 2012;41(3):409–15.
PubMedCrossRef
24.
Zhao F, Obermann S, von Wasielewski R, Haile L, Manns MP, Korangy F, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology. 2009;128(1):141–9.
PubMedCentralPubMedCrossRef
25.
De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, et al. Intratumor T helper type 2 cell infiltrate correlates with cancer-associated fibroblast thymic stromal lymphopoietin production and reduced survival in pancreatic cancer. J Exp Med. 2011;208(3):469–78.
PubMedCentralPubMedCrossRef
26.
Abdollahi A, Schwager C, Kleeff J, Esposito I, Domhan S, Peschke P, et al. Transcriptional network governing the angiogenic switch in human pancreatic cancer. Proc Natl Acad Sci U S A. 2007;104(31):12890–5.
PubMedCentralPubMedCrossRef
27.
Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.
PubMedCentralPubMedCrossRef
28.
Strouch MJ, Cheon EC, Salabat MR, et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(8):2257–65.
CrossRef
29.
Esposito I, Menicagli M, Funel N, et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol. 2004;57(6):630–6.
PubMedCentralPubMedCrossRef
30.
Loos M, Hedderich DM, Ottenhausen M, Giese NA, Laschinger M, Esposito I, et al. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer. 2009;9:463-2407-9-463.
CrossRef
31.
Tong D, Zhou Y, Chen W, Deng Y, Li L, Jia Z, et al. T cell immunoglobulin- and mucin-domain-containing molecule 3 gene polymorphisms and susceptibility to pancreatic cancer. Mol Biol Rep. 2012;39(11):9941–6.
PubMedCrossRef
32.
Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, Simon PO, Mitchem JB, Hornick JR, et al. A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs. 2013;31(3):707–13.
PubMedCentralPubMedCrossRef
33.
Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752–61.
PubMedCrossRef
34.
Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg. 2008;206(5):849–54. discussion 854-6.
PubMedCrossRef
35.
Cooper D, Ilarregui JM, Pesoa SA, Croci DO, Perretti M, Rabinovich GA. Multiple functional targets of the immunoregulatory activity of galectin-1: Control of immune cell trafficking, dendritic cell physiology, and T-cell fate. Methods Enzymol. 2010;480:199–244.
PubMedCrossRef
36.
Fitzner B, Walzel H, Sparmann G, Emmrich J, Liebe S, Jaster R. Galectin-1 is an inductor of pancreatic stellate cell activation. Cell Signal. 2005;17(10):1240–7.
PubMedCrossRef
37.
Chung JC, Oh MJ, Choi SH, Bae CD. Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma. ANZ J Surg. 2008;78(4):245–51.
PubMedCrossRef
38.
Kuramitsu Y, Taba K, Ryozawa S, Yoshida K, Zhang X, Tanaka T, et al. Identification of up- and down-regulated proteins in gemcitabine-resistant pancreatic cancer cells using two-dimensional gel electrophoresis and mass spectrometry. Anticancer Res. 2010;30(9):3367–72.
PubMed
39.
Chen R, Pan S, Ottenhof NA, de Wilde RF, Wolfgang CL, Lane Z, et al. Stromal galectin-1 expression is associated with long-term survival in resectable pancreatic ductal adenocarcinoma. Cancer Biol Ther. 2012;13(10):899–907.
PubMedCentralPubMedCrossRef
40.
Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, et al. Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer. 2009;101(10):1709–16.
PubMedCentralPubMedCrossRef
41.
Yamamoto K, Ueno T, Kawaoka T, Hazama S, Fukui M, Suehiro Y, et al. MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res. 2005;25(5):3575–9.
PubMed
42.
Ramanathan RK, Lee KM, McKolanis J, Hitbold E, Schraut W, Moser AJ, et al. Phase I study of a MUC1 vaccine composed of different doses of MUC1 peptide with SB-AS2 adjuvant in resected and locally advanced pancreatic cancer. Cancer Immunol Immunother. 2005;54(3):254–64.
PubMedCrossRef
43.
Petrulio CA, Kaufman HL. Development of the PANVAC-VF vaccine for pancreatic cancer. Expert Rev Vaccines. 2006;5(1):9–19.
PubMedCrossRef
44.
Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem JL, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol. 2009;27(13):2231–7.
PubMedCrossRef
45.
Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. 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 Oncol. 2010;28(22):3617–22.
PubMedCentralPubMedCrossRef
46.
Yamaue H, Tani T, Miyazawa M, Yamao K, Mizuno N, Okusaka T, et al. Phase II/III clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with locally advanced, metastatic, or unresectable pancreatic cancer: Pegasus-PC study. J Clin Oncol. 2013;4:abstr 223.
47.
Middleton G, Silcocks P, Cox T, Valle J, Wadsley J, Propper D, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15(8):829–40.
PubMedCrossRef
49.
Buanes T, Maurel J, Liauw W, Hebbar M, Nemunaitis J. A randomized phase III study of gemcitabine (G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreatic cancer (PC). J Clin Oncol (Meeting Abstracts) May 2009;27(no. 15S 4601).
50.
Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer. 2006;95(11):1474–82.
PubMedCentralPubMedCrossRef
51.
Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012;41(3):374–9.
PubMedCrossRef
52.
Brett BT, Smith SC, Bouvier CV, Michaeli D, Hochhauser D, Davidson BR, et al. Phase II study of anti-gastrin-17 antibodies, raised to G17DT, in advanced pancreatic cancer. J Clin Oncol. 2002;20(20):4225–31.
PubMedCrossRef
53.
Shapiro J, Marshall J, Karasek P, et al. G17DT + gemcitabine versus placebo + gemcitabine in untreated subjects with locally advanced, recurrent or metastatic adenocarcinoma of the pancreas: results of a randomized, double-blinded, multinational, multicenter study. J Clin Oncol. 2005;23(suppl):4012.
54.
Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer. 2001;92(3):441–50.
PubMedCrossRef
55.
Abou-Alfa GK, Chapman PB, Feilchenfeldt J, Brennan MF, Capanu M, Gansukh B, et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am J Clin Oncol. 2011;34(3):321–5.
PubMedCrossRef
56.
Weden S, Klemp M, Gladhaug IP, Moller M, Eriksen JA, Gaudernack G, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011;128(5):1120–8.
PubMedCrossRef
57.
Muscarella P et al. A randomized, placebo controlled, doubled, blind, multicenter phase 2 adjuvant trial of the efficacy, immunogenicity, and safety of GI-4000 plus Gem vs Gem alone in patients with resected pancreas cancer with activating Ras mutations/survival and immunology analysis of the R1 Subgroup. J Clin Oncol. 2012;30(suppl):astr #e14501.
58.
Kondo H, Hazama S, Kawaoka T, Yoshino S, Yoshida S, Tokuno K, et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 2008;28(1B):379–87.
PubMed
59.
Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, et al. Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Pancreas. 2012;41(2):195–205.
PubMedCrossRef
60.
Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol. 2001;19(1):145–56.
PubMed
61.
Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, et al. 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 Surg. 2011;253(2):328–35.
PubMedCentralPubMedCrossRef
62.
Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, et al. 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 Res. 2008;14(5):1455–63.
PubMedCentralPubMedCrossRef
63.
Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325–33.
PubMedCrossRef
64.
Kawaoka T, Oka M, Takashima M, Ueno T, Yamamoto K, Yahara N, et al. Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1. Oncol Rep. 2008;20(1):155–63.
PubMed
65.
Beatty GL. Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer. 2015 ASCO Annual Meeting; 2015.
66.
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.
PubMedCentralPubMedCrossRef
67.
Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.
PubMedCrossRef
68.
Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331(6024):1612–6.
PubMedCentralPubMedCrossRef
69.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.
PubMedCentralPubMedCrossRef
70.
Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.
PubMedCrossRef
71.
Segal NH, Anto SJ, Brahmer JR, et al. Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody. J Clin Oncol. 2014;32(5 s):abstr 3002.
72.
Plate JM, Plate AE, Shott S, Bograd S, Harris JE. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother. 2005;54(9):915–25.
PubMedCrossRef
73.
Correale P, Cusi MG, Del Vecchio MT, Aquino A, Prete SP, Tsang KY, et al. Dendritic cell-mediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro. J Immunol. 2005;175(2):820–8.
PubMedCrossRef
74.
Kershaw MH, Devaud C, John LB, Westwood JA, Darcy PK. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment. Oncoimmunology. 2013;2(9):e25962.
PubMedCentralPubMedCrossRef
75.
Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013;36(7):382–9.
PubMedCentralPubMedCrossRef
76.
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015;372(26):2509–20.
PubMedCrossRef
77.
Geynisman DM, Zha Y, Kunnavakkam R, Aklilu M, Catenacci DV, Polite BN, et al. A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma. J Immunother Cancer. 2013;1:8-1426-1-8. eCollection 2013.
78.
Schuetz T, Kaufman H, Marshall J, Safran H. Extended survival in second-line pancreatic cancer after therapeutic vaccination.2005. 16 suppl 2576. ASCO Annual Meeting.
79.
Jesus-Acosta A, O'Dwyer P, Ramanathan R, et al. A phase II study of vismodegib, a hedgehog (Hh) pathway inhibitor, combined with gemcitabine and nab-paclitaxel (nab-P) in patients (pts) with untreated metastatic pancreatic ductal adenocarcinoma (PDA). J Clin Oncol 32, 2014 (suppl 3; abstr 257). ASCO Annual Meeting.
80.
Starodub A, Ocean A, Shah M, et al. SN-38 antibody-drug conjugate (ADC) targeting Trop-2, IMMU-132, as a novel platform for the therapy of diverse metastatic solid cancers: Initial clinical results. J Clin Oncol 32:5s, 2014 (suppl; abstr 3032). ASCO Annual Meeting
81.
Nishida S, Koido S, Takeda Y, Homma S, Komita H, Takahara A, et al. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J Immunother. 2014;37(2):105–14.
PubMedCentralPubMedCrossRef
82.
Nakamura M, Wada J, Suzuki H, Tanaka M, Katano M, Morisaki T. Long-term outcome of immunotherapy for patients with refractory pancreatic cancer. Anticancer Res. 2009;29(3):831–6.
PubMed
83.
Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, et al. 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 Ther. 2008;6(B):955–64.
PubMedCentralPubMed
84.
Pecher G, Haring A, Kaiser L, Thiel E. Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunol Immunother. 2002;51(11-12):669–73.
PubMedCrossRef
85.
Koido S, Homma S, Okamoto M, Mori M, and Yoshizaki S. Dendritic cells pulsed with Wilms′ tumor gene 1 (WT1)-specific and MHC class I and II-restricted epitopes with gemcitabine induce antitumor immune responses in patients with advanced pancreatic cancer. Cancer Research. October 1, 2014;74:CT223. AACR Annual Meeting.