Pancreatic cancer: Role of the immune system in cancer progression and vaccine-based immunotherapy

Human Vaccines and Immunotherapeutics

Volumn 10, Issue 11, 2014, Pages 3354-3368

  Amedei, Amedeo ^a,b   Niccolai, Elena ^a   Prisco, Domenico ^a,b  

^a UNIVERSITY OF FLORENCE   (Italy)

^b CAREGGI UNIVERSITY HOSPITAL   (Italy)

Author keywords

Clinical trials; Immune response; Immunotherapy; Pancreatic cancer; Vaccine

Indexed keywords

ALGENPANTUCEL L; ALPHA ENOLASE; ANTINEOPLASTIC AGENT; BEVACIZUMAB; CANCER VACCINE; CEA TARGETING VACCINE; CETUXIMAB; CRS 207; DENDRITIC CELL VACCINE; GASTRIN BASED VACCINE; GM CSF SECRETING VACCINE; HSP PEPTIDE COMPLEX BASED VACCINE; KRAS TARGETING VACCINE; MATUZUMAB; MONOCLONAL ANTIBODY; MUC1 TARGETING VACCINE; PANKOMAB; PEPTIDE VACCINE; SURVIVIN TARGETING VACCINE; TELOMERASE TARGETING VACCINE; TRASTUZUMAB; UNCLASSIFIED DRUG; GVAX VACCINE; TUMOR ANTIGEN;

ADAPTIVE IMMUNITY; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER PREVENTION; CANCER SURVIVAL; CELL ACTIVITY; DRUG MECHANISM; DRUG SAFETY; EFFECTOR CELL; GENE OVEREXPRESSION; HUMAN; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; IMMUNOLOGICAL TOLERANCE; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; NATURAL KILLER CELL; NONHUMAN; OVERALL SURVIVAL; PANCREAS CANCER; PASSIVE IMMUNIZATION; PROTEIN TARGETING; REVIEW; DENDRITIC CELL; DISEASE COURSE; IMMUNOLOGY; IMMUNOTHERAPY; PANCREATIC NEOPLASMS; PROCEDURES; T LYMPHOCYTE; TUMOR ESCAPE;

ANTIBODIES, MONOCLONAL; ANTIGENS, NEOPLASM; ANTINEOPLASTIC AGENTS; CANCER VACCINES; DENDRITIC CELLS; DISEASE PROGRESSION; HUMANS; IMMUNE TOLERANCE; IMMUNOTHERAPY; PANCREATIC NEOPLASMS; T-LYMPHOCYTES; TUMOR ESCAPE;

EID: 84921803174     PISSN: 21645515     EISSN: 2164554X     Source Type: Journal    
DOI: 10.4161/hv.34392     Document Type: Review

References (155)

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90; PMID:21296855; http://dx.doi.org/10.3322/caac.20107
2. Hartwig W, Werner J, Jäger D, Debus J, Büchler MW. Improvement of surgical results for pancreatic cancer. Lancet Oncol 2013; 14:476-85; PMID:24079875; http://dx.doi.org/10.1016/S1470-2045(13)70172-4
3. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011 Dec 1;29(34):4548-54; PMID:21969517; http://dx.doi.org/10.1200/JCO.2011.36.5742
4. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, et al; Groupe Tumours Digestives of Unicancer; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011; 364:1817-25; PMID:21561347; http://dx.doi.org/10.1056/NEJMoa1011923
5. Oettle H, Riess H, Stieler JM, Heil G, Schwaner I, Seraphin J, Görner M, Mölle M, Greten TF, Lakner V, et al. Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: Outcomes From the CONKO-003 Trial. J Clin Oncol 2014 Jun 30; 32(23):2423-9. pii: JCO.2013.53.6995.
6. Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol 2012; 22:33-40; PMID: 22210179; http://dx.doi.org/10.1016/j.semcancer.2011.12.005
7. Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005; 5:263-74; PMID:15776005
8. Johnston FM, Tan MC, Tan BR Jr, Porembka MR, Brunt EM, Linehan DC, Simon PO JR, Plambeck-Suess S, Eberlein TJ, Hellstrom KE, et al. Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin Cancer Res 2009; 15:6511-18; PMID:19843662
9. Kubuschok B, Neumann F, Breit R, Sester M, Schormann C, Wagner C, Sester U, Hartmann F, Wagner M, Remberger K, et al. Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer. Clin Cancer Res 2006; 12:1365-1372; PMID:16489095
10. Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N, Abeno S, Ikeba A, Takashima S, Tsujie M, et al. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 2004; 95:583-87; PMID:15245594
11. Ueda M, Miura Y, Kunihiro O, Ishikawa T, Ichikawa Y, Endo I, Sekido H, Togo S, Shimada H. MUC1 overexpression is the most reliable marker of invasive carcinoma in intraductal papillary-mucinous tumor (IPMT). Hepato-Gastroenterology 2005; 52:398-403; PMID:15816444
12. Seki K, Suda T, Aoyagi Y, Sugawara S, Natsui M, Motoyama H, Shirai Y, Sekine T, Kawai H, Mita Y, et al. Diagnosis of pancreatic adenocarcinoma by detection of human telomerase reverse transcriptase-messenger RNA in pancreatic juice with sample qualification. Clin Cancer Res 2001; 7:1976-81; PMID:11448913
13. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E, Gaudernack G. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 1995; 346:1399-1400, 1995; PMID:7475823
14. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen surviving. Cancer Immunol Immunother 2006; 55:1294-1298; PMID:16315030
15. Yamaguchi K, Enjoji M, Tsuneyoshi M. Pancreatoduodenal carcinoma: a clinicopathologic study of 304 patients and immunohistochemical observation for CEA and CA19-9. J Surg Oncol 1991; 47:148-54; PMID:2072697
16. Komoto M, Nakata B, Amano R, Yamada N, Yashiro M, Ohira M, Wakasa K, Hirakawa K. HER2 overexpression correlates with survival after curative resection of pancreatic cancer. Cancer Sci 2009; 100:1243-1247; PMID:19432892
17. Maacke H, Kessler A, Schmiegel W, Roeder C, Vogel I, Deppert W, Kalthoff H. Overexpression of p53 protein during pancreatitis. Br J Cancer 1997; 75:1501-04; PMID:9166944
18. Cappello P, Tomaino B, Chiarle R, Ceruti P, Novarino A, Castagnoli C, Migliorini P, Perconti G, Giallongo A, Milella M, et al. An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer 2009; 125:639-48; PMID:19425054
19. Hamanaka Y, Suehiro Y, Fukui M, Shikichi K, Imai K, Hinoda Y. Circulating anti-MUC1 IgG antibodies as a favorable prognostic factor for pancreatic cancer. Int J Cancer 2003; 103:97-100; PMID:12455059
20. Tewari N, Zaitoun AM, Arora A, Madhusudan S, Ilyas M, Lobo DN. The presence of tumour-associated lymphocytes confers a good prognosis in pancreatic ductal adenocarcinoma: an immunohistochemical study of tissue microarrays. BMC Cancer 2013; 13:436; PMID:24063854
21. Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010; 59:1593-600; http://dx.doi.org/10.1007/s00262-010-0855-8; PMID:20414655
22. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 2011; 60:1419-30; PMID:21644036.; http://dx.doi.org/10.1007/s00262-011-1028-0
23. Zhao F, Obermann S, von Wasielewski R, Haile L, Manns MP, Korangy F, Greten TF. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology 2009; 128:141-9; PMID:19689743; http://dx.doi.org/10.1111/j.1365-2567.2009.03105.x
24. Schmieder A, Michel J, Schönhaar K, Goerdt S, Schledzewski K. Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol 2012; 22:289-97; PMID:22349514; http://dx.doi.org/10.1016/j.semcancer.2012.02.002
25. Van Overmeire E, Laoui D, Keirsse J, Van Ginderachter JA, Sarukhan A. Mechanisms Driving Macrophage Diversity and Specialization in Distinct Tumor Microenvironments and Parallelisms with Other Tissues. Front Immunol 2014; 5:127; PMID:24723924
26. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 2004; 57:630-6; PMID:15166270
27. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S. Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 2011; 167:e211-9; PMID:19765725; http://dx.doi.org/10.1016/j.jss.2009.05.026
28. Nurieva R, Wang J, Sahoo A. T-cell tolerance in cancer. Immunotherapy 2013; 5:513-31; PMID: 23638746; http://dx.doi.org/10.2217/imt.13.33
29. Savage PA, Malchow S, Leventhal DS. Basic principles of tumor-associated regulatory T cell biology. Trends Immunol 2013; 34:33-40; PMID:22999714; http://dx.doi.org/10.1016/j.it.2012.08.005
30. Ikemoto T, Yamaguchi T, Morine Y, Imura S, Soejima Y, Fujii M, Maekawa Y, Yasutomo K, Shimada M. Clinical roles of increased populations of Foxp3+CD4+ T cells in peripheral blood from advanced pancreatic cancer patients. Pancreas 2006; 33:386-90; PMID:17079944
31. Amedei A, Niccolai E, Benagiano M, Della Bella C, Cianchi F, Bechi P, Taddei A, Bencini L, Farsi M, Cappello P, et al. 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 Immunother 2013; 62:1249-60; PMID:23640603; http://dx.doi.org/10.1007/s00262-013-1429-3
32. Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3 +regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 2006; 12:5423-34; PMID:17000676
33. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Hirooka S, Yamaki S, Yui R, Yamao J, Kim S, Kwon AH. Circulating CD4+CD25 +regulatory T cells in patients with pancreatic cancer. Pancreas 2012; 41:409-15; PMID:22158072; http://dx.doi.org/10.1097/MPA.0b013e3182373a66
34. Yamamoto T, Yanagimoto H, Satoi S, Toyokawa H, Yamao J, Kim S, Terakawa N, Takahashi K, Kwon AH. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res 2012; 173:299-308; PMID:21195425; http://dx.doi.org/10.1016/j.jss.2010.09.027
35. Tjomsland V, Spa˚ngeus A, Sandström 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:e13441; PMID:20976171; http://dx.doi.org/10.1371/journal.pone.0013441
36. Pandha H, Rigg A, John J, Lemoine N. Loss of expression of antigen presenting molecules in human pancreatic cancer and pancreatic cancer cell lines. Clin Exp Immunol 2007; 148:127-35; PMID:17302733
37. Aparicio-Pagés MN, Verspaget HW, Peña AS, Lamers CB. Natural killer cell activity in patients with adenocarcinoma in the upper gastrointestinal tract. J Clin Lab Immunol 1991; 35:27-32; PMID:1668287
38. Duan X, Deng L, Chen X, Lu Y, Zhang Q, Zhang K, Hu Y, Zeng J, Sun W. Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol 2011; 28:466-74; PMID:20354827; http://dx.doi.org/10.1007/s12032-010-9480-9
39. Davis M, Conlon K, Bohac GC, Barcenas J, Leslie W, Watkins L, Lamzabi I, Deng Y, Li Y, Plate JM. Effect of pemetrexed on innate immune killer cells and adaptive immune T cells in subjects with adenocarcinoma of the pancreas. J Immunother 2012; 35:629-40; PMID:22996369
40. Schmitz-Winnenthal FH, Volk C, Z'graggen K, Galindo L, Nummer D, Ziouta Y, Bucur M, Weitz J, Schirrmacher V, Büchler MW, et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005; 65:10079-87; PMID:16267034
41. + tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 2004; 28:e26-31; PMID:14707745
42. De Monte L, Reni M, Tassi E, Clavenna D, Papa I, Recalde H, Braga M, Di Carlo V, Doglioni C, Protti MP. 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; 208:469-78; PMID:21339327; http://dx.doi.org/10.1084/jem.20101876
43. Tassi E, Gavazzi F, Albarello L, Senyukov V, Longhi R, Dellabona P, Doglioni C, Braga M, Di Carlo V, Protti MP. Carcinoembryonic antigen-specific but not antiviral CD4+ T cell immunity is impaired in pancreatic carcinoma patients. J Immunol 2008; 181:6595-603; PMID:19798410
44. Inman BA, Frigola X, Dong H, Kwon ED. Costimulation, coinhibition and cancer. Curr Cancer Drug Targets 2007; 7:15-30; PMID:17305475
45. Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, Hu Z, Zhang J, Jiang G, Zheng S. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J Cancer Res Clin Oncol 2008; 134:1021-7; PMID:18347814; http://dx.doi.org/10.1007/s00432-008-0364-8
46. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, 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; 13:2151-7; PMID:17404099
47. Shoji Y, Miyamoto M, Ishikawa K, Yoshioka T, Mishra R, Ichinokawa K, Matsumura Y, Itoh T, Shinohara T, Hirano S, et al. The CD40-CD154 interaction would correlate with proliferation and immune escape in pancreatic ductal adenocarcinoma. J Surg Oncol 2011; 103:230-8; PMID:21337550; http://dx.doi.org/10.1002/jso.21812
48. Loos M, Hedderich DM, Ottenhausen M, Giese NA, Laschinger M, Esposito I, Kleeff J, Friess H. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer 2009; 9:463; PMID:20035626; http://dx.doi.org/10.1186/1471-2407-9-463
49. Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, Kanehiro H, Konishi N, Yagita H, Nakajima Y. Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer 2009; 101:1709-16; PMID:19844235; http://dx.doi.org/10.1038/sj.bjc.6605375
50. Hinz S, Pagerols-Raluy L, Oberg HH, Ammerpohl O, Grüssel S, Sipos B, Grützmann R, Pilarsky C, Ungefroren H, Saeger HD, et al. Foxp3 expression in pancreatic carcinoma cells as a novel mechanism of immune evasion in cancer. Cancer Res 2007; 67:8344-50; PMID:17804750
51. Teraoka H, Sawada T, Yamashita Y, Nakata B, Ohira M, Ishikawa T, Nishino H, Hirakawa K. TGF-beta1 promotes liver metastasis of pancreatic cancer by modulating the capacity of cellular invasion. Int J Oncol 2001; 19:709-15; PMID:11562745
52. Bellone G, Turletti A, Artusio E, Mareschi K, Carbone A, Tibaudi D, Robecchi A, Emanuelli G, Rodeck U. Tumor-associated transforming growth factor-beta and interleukin-10 contribute to a systemic Th2 immune phenotype in pancreatic carcinoma patients. Am J Pathol 1999; 155:537-47; PMID:10433946
53. Bellone G, Smirne C, Mauri FA, Tonel E, Carbone A, Buffolino A, Dughera L, Robecchi A, Pirisi M, Emanuelli G. Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival. Cancer Immunol Immunother 2006; 55:684-98; PMID:16094523
54. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, Orabona C, Bianchi R, Belladonna ML, Volpi 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; 176:6752-61; PMID:16709834
55. Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, Brody JR. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg 2008; 206:849-54; PMID:18471709; http://dx.doi.org/10.1016/j.jamcollsurg.2007.12.014
56. Söderlund J, Erhardt S, Kast RE. Acyclovir inhibition of IDO to decrease Tregs as a glioblastoma treatment adjunct. J Neuroinflammation 2010; 7:44; PMID:20691089; http://dx.doi.org/10.1186/1742-2094-7-44
57. 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; PMID:20816212; http://dx.doi.org/10.1016/S0076-6879(10)80011-4
58. Kuramitsu Y, Taba K, Ryozawa S, Yoshida K, Zhang X, Tanaka T, Maehara S, Maehara Y, Sakaida I, Nakamura K. Identification of up- and down-regulated proteins in gemcitabine-resistant pancreatic cancer cells using two-dimensional gel electrophoresis and mass spectrometry. Anticancer Res 2010; 30:3367-72; PMID:20944110
59. Chung JC, Oh MJ, Choi SH, Bae CD. Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma. ANZ J Surg 2008; 78:245-51; PMID:18366394; http://dx.doi.org/10.1111/j.1445-2197.2008.04429.x
60. Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ, et al. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11bCLy-6GC myeloid cells. J Immunol 2010; 185:1383-92; PMID:20574007; http://dx.doi.org/10.4049/jimmunol.0903275
61. Peng W, Wang HY, Miyahara Y, Peng G, Wang RF. Tumor-associated galectin-3 modulates the function of tumor-reactive T cells. Cancer Res 2008; 68:7228-36; PMID:18757439; http://dx.doi.org/10.1158/0008-5472.CAN-08-1245
62. Xie L, Ni WK, Chen XD, Xiao MB, Chen BY, He S, Lu CH, Li XY, Jiang F, Ni RZ. The expressions and clinical significances of tissue and serum galectin-3 in pancreatic carcinoma. J Cancer Res Clin Oncol 2012; 138:1035-43; PMID:22367363; http://dx.doi.org/10.1007/s00432-012-1178-2
63. Song S, Ji B, Ramachandran V, Wang H, Hafley M, Logsdon C, Bresalier RS. Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signalling. PLoS One 2012; 7:e42699; PMID:22900040; http://dx.doi.org/10.1371/journal.pone.0042699
64. Jiang XR, Song A, Bergelson S, Arroll T, Parekh B, May K, Chung S, Strouse R, Mire-Sluis A, Schenerman M. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat Rev Drug Discov 2011; 10:101-111; PMID: 21283105.; http://dx.doi.org/10.1038/nrd3365
65. Hellstrom I, Friedman E, Verch T, Yang Y, Korach J, Jaffar J, Swisher E, Zhang B, Ben-Baruch G, Tan MC, et al. Anti-mesothelin antibodies and circulating mesothelin relate to the clinical state in ovarian cancer patients. Cancer Epidemiol, Biomarkers & Prevention 2008; 17:1520-1526; PMID:18559570; http://dx.doi.org/10.1158/1055-9965.EPI-08-0039
66. Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, Pastan I. Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clin Cancer Res 2005; 11:3814-3820; PMID:15897581; http://dx.doi.org/10.1158/1078-0432.CCR-04-2304
67. Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelinexpressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res 2007; 13:5144-5149; PMID:17785569; http://dx.doi.org/10.1158/1078-0432.CCR-07-0869
68. Filpula D, Zhao H. Releasable PEGylation of proteins with customized linkers. Adv Drug Delivery Rev 2008; 60:29-49; PMID:17884239; http://dx.doi.org/10.1016/j.addr.2007.02.001
69. Kreitman RJ, Hassan R, Fitzgerald DJ, Pastan I. Phase I trial of continuous infusion antimesothelin recombinant immunotoxin SS1P. Clin Cancer Res 2009; 15:5274-5279; PMID:19671873; http://dx.doi.org/10.1158/1078-0432.CCR-09-0062
70. Hassan R, Cohen SJ, Phillips M, Pastan I, Sharon E, Kelly RJ, Schweizer C, Weil S, Laheru D. Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelinexpressing cancers. Clin Cancer Res 2010 Dec 15;16(24):6132-8; PMID:21037025; http://dx.doi.org/10.1158/1078-0432.CCR-10-2275. Epub 2010 Oct 29
71. Feng Y, Xiao X, Zhu Z, Streaker E, Ho M, Pastan I, Dimitrov DS. A novel human monoclonal antibody that binds with high affinity to mesothelin-expressing cells and kills them by antibody-dependent cell-mediated cytotoxicity. Mol Cancer Therap 2009; 8:1113-1118; PMID:19417159; http://dx.doi.org/10.1158/1535-7163.MCT-08-0945
72. Ho M, Feng M, Fisher RJ, Rader C, Pastan I. A novel high affinity human monoclonal antibody to mesothelin. Int J Cancer 2011; 128:2020-2030; PMID:20635390; http://dx.doi.org/10.1002/ijc.25557
73. Yamasaki H, Ikeda S, Okajima M, Miura Y, Asahara T, Kohno N, Shimamoto F. Expression and localization of MUC1, MUC2, MUC5AC and small intestinal mucin antigen in pancreatic tumors. Int J Oncol 2004; 24:107-113; PMID:14654947; http://dx.doi.org/10.3892/ijo.24.1.107
74. Qu CF, Li Y, Song YJ, Rizvi SM, Raja C, Zhang D, Samra J, Smith R, Perkins AC, Apostolidis C, et al. MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by (213)Bi-C595 radioimmunoconjugate. British J Cancer 2004; 91:2086-2093; PMID:15599383; http://dx.doi.org/10.1038/sj.bjc.6602232
75. Levi E, Klimstra DS, Andea A, Basturk O, Adsay NV. MUC1 and MUC2 in pancreatic neoplasia. J Clin Pathol 2004; 57:456-462; PMID:15113850; http://dx.doi.org/10.1136/jcp.2003.013292
76. Tsutsumida H, Swanson BJ, Singh PK, Caffrey TC, Kitajima S, Goto M, Yonezawa S, Hollingsworth MA. RNA interference suppression of MUC1 reduces the growth rate and metastatic phenotype of human pancreatic cancer cells. Clin Cancer Res 2006; 12:2976-2987; PMID:16707592; http://dx.doi.org/10.1158/1078-0432.CCR-05-1197
77. Gold DV, Modrak DE, Schutsky K, Cardillo TM. Combined 90Yttrium-DOTA-labeled PAM4 antibody radioimmunotherapy and gemcitabine radiosensitization for the treatment of a human pancreatic cancer xenograft. Int J Cancer 2004; 109:618-626; PMID:14991585; http://dx.doi.org/10.1002/ijc.20004
78. Danielczyk A, Stahn R, Faulstich D, Löffler A, Märten A, Karsten U, Goletz S. PankoMab: a potent new generation anti-tumour MUC1 antibody. Cancer Immunol, Immunother 2006; 55: 1337-1347; PMID:16485130; http://dx.doi.org/10.1007/s00262-006-0135-9
79. Fan XN, Karsten U, Goletz S, Cao Y. Reactivity of a humanized antibody (hPankoMab) towards a tumor-related MUC1 epitope (TA-MUC1) with various human carcinomas. Pathol, Res Practice 2010; 206:585-589; PMID:20400237; http://dx.doi.org/10.1016/j.prp.2010.03.006
80. Pratesi G, Petrangolini G, Tortoreto M, Addis A, Zunino F, Calcaterra C, Merlo A, Tagliabue E, Menard S, Balsari A. Antitumor efficacy of trastuzumab in nude mice orthotopically xenografted with human pancreatic tumor cells expressing low levels of HER-2/neu. J Immunother 2008; 31:537-544; PMID:18528301; http://dx.doi.org/10.1097/CJI.0b013e31817c37ff
81. Saeki H, Yanoma S, Takemiya S, Sugimasa Y, Akaike M, Yukawa N, Rino Y, Imada T. Antitumor activity of a combination of trastuzumab (Herceptin) and oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2- overexpressing pancreatic cancer. Oncol Rep 2007; 18:433-439; PMID:17611667; http://dx.doi.org/10.3892/or.18.2.433
82. Larbouret C, Robert B, Navarro-Teulon I, Thèzenas S, Ladjemi MZ, Morisseau S, Campigna E, Bibeau F, Mach JP, Pèlegrin A, et al. In vivo therapeutic synergism of anti-epidermal growth factor receptor and anti-HER2 monoclonal antibodies against pancreatic carcinomas," Clin Cancer Res 2007; vol. 13, no. 11, pp. 3356-3362; PMID:17545543; http://dx.doi.org/10.1158/1078-0432.CCR-06-2302
83. Larbouret C, Robert B, Bascoul-Mollevi C, Penault-Llorca F, Ho-Pun-Cheung A, Morisseau S, Navarro-Teulon I, Mach JP, Pèlegrin A, Azria D. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts. Ann Oncol 2010; 21:98-103; PMID:19889608; http://dx.doi.org/10.1093/annonc/mdp496
84. Blumenthal RD, Osorio L, Hayes MK, Horak ID, Hansen HJ, Goldenberg DM. Carcinoembryonic antigen antibody inhibits lung metastasis and augments chemotherapy in a human colonic carcinoma xenograft. Cancer Immunol, Immunother 2005; 54:315-327; PMID:15592930; http://dx.doi.org/10.1007/s00262-004-0597-6
85. A Phase I/II Study of Radioimmunotherapy With 90Y-Humanized MN-14 IgG Administered as a Single Dose to Patients With Refractory Advanced/Metastatic Pancreatic Carcinoma (NCT00041639). Available at http:clinicaltrials.gov
86. Lemoine NR, Hughes CM, Barton CM, Poulsom R, Jeffery RE, Köppel G, Hall PA, Gullick WJ. The epidermal growth factor receptor in human pancreatic cancer. J Pathol 1992; 166:166:7-12; PMID:1538276
87. Yamanaka Y, Friess H, Kobrin MS, Buchler M, Beger HG, Korc M. Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res 1993; 13:565-569; PMID:8317885
88. Bruns CJ, Solorzano CC, Harbison MT, Ozawa S, Tsan R, Fan D, Abbruzzese J, Traxler P, Buchdunger E, Radinsky R, et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 2000; 60:2926-2935; PMID:10850439
89. Ng SS, Tsao MS, Nicklee T, Hedley DW. Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol Cancer Therap 2002; 1:777-783; PMID:12492110
90. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. Int J Oncol 2005; 23:2445-2459; PMID:15753456; http://dx.doi.org/10.1200/JCO.2005.11.890
91. Philip PA, Benedetti J, Corless CL, Wong R, O'Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, et al. Phase III Study Comparing Gemcitabine Plus Cetuximab Versus Gemcitabine in Patients With Advanced Pancreatic Adenocarcinoma: Southwest Oncology Group- Directed Intergroup Trial S0205. J Clin Oncol 2010; 28: 3605-3610; PMID:20606093; http://dx.doi.org/10.1200/JCO.2009.25.7550
92. Krempien R, Muenter MW, Huber PE, Nill S, Friess H, Timke C, Didinger B, Buechler P, Heeger S, Herfarth KK, et al. Cetuximab in combination with intensity modulated radiotherapy (IMRT) and gemcitabine for patients with locally advanced pancreatic cancer: A prospective phase II trial [PARC-Study ISRCTN56652283]. J Clin Oncol 2007; 25:4573; PMID:16219105; http://dx.doi.org/10.1186/1471-2407-5-131
93. Bangard C, Gossmann A, Papyan A, Tawadros S, Hellmich M, Bruns CJ. Magnetic resonance imaging in an orthotopic rat model: blockade of epidermal growth factor receptor with EMD72000 inhibits human pancreatic carcinoma growth. Int J Cancer 2005; 114:131-138; PMID:15523683; http://dx.doi.org/10.1002/ijc.20696
94. Graeven U, Kremer B, Südhoff T, Killing B, Rojo F, Weber D, Tillner J, Unal C, Schmiegel W. Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. British J Cancer 2006; 94:1293-1299; PMID:16622465; http://dx.doi.org/10.1038/sj.bjc.6603083
95. Korc M. Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2003; 2:8; PMID:12556241; http://dx.doi.org/10.1186/1476-4598-2-8
96. Karayiannakis AJ, Bolanaki H, Syrigos KN, Asimakopoulos B, Polychronidis A, Anagnostoulis S, Simopoulos C. Serum vascular endothelial growth factor levels in pancreatic cancer patients correlate with advanced and metastatic disease and poor prognosis. Cancer Lett 2003; 194:119-124; PMID:12706865; http://dx.doi.org/10.1016/S0304-3835(03)00047-8
97. Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23:8033-8040; PMID:16258101; http://dx.doi.org/10.1200/JCO.2005.01.9661
98. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, Innocenti F, Mulcahy MF, O'Reilly E, Wozniak TF, 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 2007; 28:3617-3622; PMID:20606091; http://dx.doi.org/10.1200/JCO.2010.28.1386
99. Bruckner HW, Hrehorovich VR, Sawhney HS. Bevacizumab as treatment for chemotherapyresistant pancreatic cancer. Anticancer Res 2005; 25:3637-3639; PMID:16101193
100. Hensler T, Hecker H, Heeg K, Heidecke CD, Bartels H, Barthlen W, Wagner H, Siewert JR, Holzmann B. Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun 1997; 65:2283-91; PMID:9169765
101. Shakhar G, Ben-Eliyahu S. Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients?. Ann Surg Oncol 2003; 10:972-92; PMID:14527919
102. Weighardt H, Heidecke CD, Emmanuilidis K, Maier S, Bartels H, Siewert JR, Holzmann B. Sepsis after major visceral surgery is associated with sustained and interferon-g resistant defects of monocyte cytokine production. Surgery. 2000; 127:309-15; PMID:10715987
103. Koido S, Hara E, Homma S, Namiki Y, Komita H, Takahara A, Nagasaki E, Ito M, Sagawa Y, Mitsunaga M, et al. Dendritic/pancreatic carcinoma fusions for clinical use: comparative functional analysis of healthy- versus patient-derived fusions. Clin Immunol 2010; 135:384-400; PMID:20226739
104. Koido S, Hara E, Homma S, Torii A, Toyama Y, Kawahara H, Watanabe M, Yanaga K, Fujise K, Tajiri H, et al. Dendritic cells fused with allogeneic colorectal cancer cell line present multiple colorectal cancerspecific antigens and induce antitumor immunity against autologous tumor cells. Clin Cancer Res 2005; 11:7891-900; PMID:16278414
105. Saito H, Dubsky P, Dantin C, Finn OJ, Banchereau J, Palucka AK. Cross-priming of cyclin B1, MUC-1 and survivin-specific CD8+ T cells by dendritic cells loaded with killed allogeneic breast cancer cells. Breast Cancer Res 2006; 8:R65; PMID:17129372
106. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, et al. Novel allogeneic granulocyte-macrophage colony-stimulating factorsecreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001; 19:145-56; PMID:11134207
107. Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, 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; 19:145-56; PMID:11134207
108. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, et al. Allogeneic granulocyte macrophage colonystimulating 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; 14:1455-63; PMID:18316569; http://dx.doi.org/10.1158/1078-0432.CCR-07-0371
109. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. 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 U S A 1993; 90:3539-43; PMID:8097319
110. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, et al. A lethally irradiated allogeneic granulo-cyte- macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg 2011; 253:328-35; PMID:21217520; http://dx.doi.org/10.1097/SLA.0b013e3181fd271c
111. Dung TLe, Andrea Wang-Gillam, Vincent J Picozzi, Tim F Greten, Todd S Crocenzi, Gregory M Springett, Michael Morse, Herbert Zeh, Deirdre Jill Cohen, Robert Lance Fine, et al. Brockstedt, Elizabeth M. Jaffee; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Washington University School of Medicine in St. Louis, St. Louis, MO; Virginia Mason Medical Center, Seattle, WA; National Cancer Institute, Bethesda, MD; Providence Cancer Center, Portland, OR; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Duke University Medical Center, Durham, NC; University of Pittsburgh Medical Center, Pittsburgh, PA; New York University Cancer Institute, New York, NY; Columbia University, New York, NY; Aduro BioTech, Inc., Berkeley, CA Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer. J Clin Oncol 31, 2013 (suppl; abstr 4040∧).
112. ClinicalTrials.gov identifier:NCT00727441.
113. Dung T, Wang-Gillam A, Picozzi Jr V, Greten TF, Crocenzi TS, Springett GM, Morse M, Zeh H, Cohen DJ, Fine RL, et al. A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results. J Clin Oncol 2014; 32(suppl 3):Abstract 177.
114. Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, Rocha-Lima CS, Safran H, Lenz HJ, Chiorean EG. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg 2013; 17:94-100; PMID:23229886; http://dx.doi.org/10.1007/s11605-012-2064-6
115. Adsay NV, Basturk O, Cheng JD, Andea AA. Ductal neoplasia of the pancreas: nosologic, clinicopathologic, and biologic aspects. Semin Radiat Oncol 2005; 15:254-64; PMID:16183479.; http://dx.doi.org/10.1016/j.semradonc.2005.04.001
116. Gaudernack G. Prospects for vaccine therapy for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006; 20:299-314; PMID:16549329
117. Capello M, Ferri-Borgogno S, Cappello P, Novelli F. α-Enolase: a promising therapeutic and diagnostic tumor target. FEBS J 2011; 278:1064-74; PMID:21261815; http://dx.doi.org/10.1111/j.1742-4658.2011.08025.x
118. Purcell AW, McCluskey J, Rossjohn J. More than one reason to rethink the use of peptides in vaccine design. Nat Rev Drug Discov 2007; 6:404-14; PMID:17473845
119. Bijker MS, Melief CJ, Offringa R, van der Burg SH. Design and development of synthetic peptide vaccines: past, present and future. Expert Rev Vaccines 2007; 6:591-603; PMID:17669012
120. Kanodia S, Kast WM. Peptide-based vaccines for cancer: realizing their potential. Expert Review of Vaccines 2008; 7:1533-45; PMID:19053209
121. Voskens CJ, Strome SE, Sewell DA. Synthetic pep-tide- based cancer vaccines: lessons learned and hurdles to overcome. Current Molecular Medicine 2009; 9:683-93; PMID:19689295
122. Mocellin S, Pilati P, Nitti D. Peptide-based anticancer vaccines: recent advances and future perspectives. Curr Med Chem 2009; 16:4779-96; PMID:19929787
123. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Gedde-Dahl T 3rd, Stokke KT, Sølheim BG, Egge TS, Søreide O, Thorsby E, et al. Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study. Int J Cancer 1996; 65:450-3; PMID:8621226
124. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Søreide O, Thorsby E, Gaudernack G. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 1995; 346:1399-400; PMID:7475823
125. Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Søreide O, Eriksen JA, Møller M, Baksaas I, Lothe RA, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colonystimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer 2001; 92:441-50; PMID:11291084
126. Abou-Alfa GK, Chapman PB, Feilchenfeldt J, Brennan MF, Capanu M, Gansukh B, Jacobs G, Levin A, Neville D, Kelsen DP, et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am J Clin Oncol 2011; 34:321-5; PMID:20686403; http://dx.doi.org/10.1097/COC.0b013e3181e84b1f
127. Bernhardt SL, Gjertsen MK, Trachsel S, Møller M, Eriksen JA, Meo M, Buanes T, Gaudernack G. Telomerase peptide vaccination of patients with nonresectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer 2006; 95:1474-82; PMID:17060934
128. Gunturu KS, Rossi GR, Saif MW. Immunotherapy updates in pancreatic cancer: are we there yet? Ther Adv Med Oncol 2013; 5:81-9; PMID:23323149; http://dx.doi.org/10.1177/1758834012462463
129. Monstein HJ, Ohlsson B, Axelson J. Differential expression of gastrin, cholecystokinin-A and cholecystokinin-B receptor mRNA in human pancreatic cancer cell lines. Scand J Gastroenterol 2001; 36:738-43; PMID:11444473
130. Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, Whitehead A, Takhar A, Rowlands BJ, Beckingham IJ. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas 2012; 41:374-9; PMID:22228104; http://dx.doi.org/10.1097/MPA.0b013e31822ade7e
131. Satoh K, Kaneko K, Hirota M, Masamune A, Satoh A, Shimosegawa T. Expression of survivin is correlated with cancer cell apoptosis and is involved in the development of human pancreatic duct cell tumors. Cancer 2001; 92(2):271-8; PMID:11466679
132. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC. Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 2006; 55:1294-8; PMID:16315030
133. Kameshima H, Tsuruma T, Kutomi G, Shima H, Iwayama Y, Kimura Y, Imamura M, Torigoe T, Takahashi A, Hirohashi Y, et al. Immunotherapeutic benefit of α-interferon (IFNa) in survivin2B-derived peptide vaccination for advanced pancreatic cancer patients. Cancer Sci 2013; 104:124-9; PMID: 23078230; http://dx.doi.org/10.1111/cas.12046
134. Fałkowska-Podstawka M, Wernicki A. Heat shock proteins in health and disease. Pol J Vet Sci 2003; 6:61-70; PMID:12675471
135. Maki RG, Livingston PO, Lewis JJ, Janetzki S, Klimstra D, Desantis D, Srivastava PK, Brennan MF. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig Dis Sci 2007; 52:1964-72; PMID:17420942
136. Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, Kim DW, Marshall J. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med 2007; 5:60; PMID:18039393
137. Arlen PM, Gulley JL, Madan RA, Hodge JW, Schlom J. Preclinical and clinical studies of recombinant poxvirus vaccines for carcinoma therapy. Crit Rev Immunol 2007; 27:451-62; PMID:18197807
138. Cappello P, Tomaino B, Chiarle R, Ceruti P, Novarino A, Castagnoli C, Migliorini P, Perconti G, Giallongo A, Milella M, et al. An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer 2009; 125:639-48; PMID:19425054; http://dx.doi.org/10.1002/ijc.24355
139. Tomaino B, Cappello P, Capello M, Fredolini C, Sperduti I, Migliorini P, Salacone P, Novarino A, Giacobino A, Ciuffreda L, et al. Circulating autoantibodies to phosphorylated a-enolase are a hallmark of pancreatic cancer. J Proteome Res 2011; 10:105-12; PMID:20455595; http://dx.doi.org/10.1021/pr100213b
140. Pérez-Mancera PA, Guerra C, Barbacid M, Tuveson DA. What we have learned about pancreatic cancer from mouse models. Gastroenterology 2012; 142:1079-92; PMID:22406637; http://dx.doi.org/10.1053/j.gastro.2012.03.002
141. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7:469-83; PMID:15894267
142. Cappello P, Rolla S, Chiarle R, Principe M, Cavallo F, Perconti G, Feo S, Giovarelli M, Novelli F. Vaccination with ENO1 DNA prolongs survival of genetically engineered mice with pancreatic cancer. Gastroenterology 2013; 144:1098-106; PMID: 23333712; http://dx.doi.org/10.1053/j.gastro.2013.01.020
143. Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, Geller BA, Schmotzer A, Potter DP, Whiteside T, 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; 6:955-64; PMID:19129927
144. Kimura Y, Tsukada J, Tomoda T, Takahashi H, Imai K, Shimamura K, Sunamura M, Yonemitsu Y, Shimodaira S, Koido S, 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; 41:195-205; PMID:21792083; http://dx.doi.org/10.1097/MPA.0b013e31822398c6
145. Goggins M, Kern SE, Offerhaus JA, Hruban RH. Progress in cancer genetics: lessons from pancreatic cancer. Ann Oncol 1999; 4:4-8; PMID:10436774
146. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, Allison JP. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008; 68:889-92; PMID:18245491; http://dx.doi.org/10.1158/0008-5472.CAN-07-3095
147. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363:711-23; PMID:20525992; http://dx.doi.org/10.1056/NEJMoa1003466
148. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54; PMID:22658127; http://dx.doi.org/10.1056/NEJMoa1200690
149. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012; 366:2455-65; PMID:22658128; http://dx.doi.org/10.1056/NEJMoa1200694
150. Zheng L, Xue J, Jaffee EM, Habtezion A. Role of immune cells and immune-based therapies in pancreatitis and pancreatic ductal adenocarcinoma. Gastroenterology 2013; 144:1230-40; PMID:23622132; http://dx.doi.org/10.1053/j.gastro.2012.12.042
151. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, Sherry RM, Topalian SL, Yang JC, Lowy I, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010; 33:828-33; PMID:20842054; http://dx.doi.org/10.1097/CJI.0b013e3181eec14c
152. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 2012; 24:207-12; PMID:22236695; http://dx.doi.org/10.1016/j.coi.2011.12.009
153. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, Zheng L, Diaz LA Jr, Donehower RC, Jaffee EM, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013; 36:382-9; PMID:23924790; http://dx.doi.org/10.1097/CJI.0b013e31829fb7a2
154. Bazhin AV, Shevchenko I, Umansky V, Werner J, Karakhanova S. Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy. Cancer Immunol Immunother 2014; 63:59-65; PMID:24129765; http://dx.doi.org/10.1007/s00262-013-1485-8
155. Niccolai E, Prisco D, D'Elios MM, Amedei A. What is recent in pancreatic cancer immunotherapy? Biomed Res Int 2013; 2013:492372; PMID: 23509731; http://dx.doi.org/10.1155/2013/492372