Pancreatic Cancer pp 1269-1318 | Cite as

Vaccine Therapy and Immunotherapy for Pancreatic Cancer

  • Lei Zheng
  • Elizabeth M. Jaffee
Reference work entry


Recent advances in the tumor immunology field of research have enriched our knowledge of how tumor cells initially evade immune surveillance and how existing tumors actively suppress immune recognition of their progression. Based on these advances, strategies for immunotherapy have been developed to enhance antitumor immunity and to target the mechanisms underlying tumor evasion and immune tolerance. These immunotherapy strategies have been employed in the design of novel treatments for pancreatic cancer and are being tested in preclinical studies and human clinical trials. Evidence of immune activation has been demonstrated in a number of these studies, and in some cases, correlated with clinical responses. However, a number of challenges must be addressed before the true potential of immune based therapies can be determined. Consequently, future studies need to focus on identifying new pancreatic cancer associated antigens, and on identifying and targeting the immune checkpoints that inhibit effective immune cell activation. In addition, the development of these new therapies will require designing clinical trials that efficiently assess combinations of biologics that target multiple immune pathways, and incorporate validated predictors of immune response. Finally, demonstrating the success of these new therapies will likely require establishing new criteria to evaluate clinical responses that are associated with immune mediated mechanisms of tumor control.


Pancreatic Cancer Human Leukocyte Antigen Tumor Antigen Pancreatic Cancer Patient Immune Checkpoint 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 1998;392:245–252.CrossRefPubMedGoogle Scholar
  2. 2.
    Schmitz-Winnenthal FH, Volk C, Z’Graggen K, Galindo L, Nummer D, Ziouta Y, Bucur M, Weitz J, Schirrmacher V, Buchler MW, Beckhove P: High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res 2005;65:10079–10087.CrossRefPubMedGoogle Scholar
  3. 3.
    Klein G: Immune surveillance – a powerful mechanism with a limited range. Natl Cancer Inst Monogr 1976;44:109–113.PubMedGoogle Scholar
  4. 4.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD: Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991–998.CrossRefPubMedGoogle Scholar
  5. 5.
    Bierie B, Moses HL: Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 2006;6:506–520.CrossRefPubMedGoogle Scholar
  6. 6.
    Goggins M, Kern SE, Offerhaus JA, Hruban RH: Progress in cancer genetics: lessons from pancreatic cancer. Ann Oncol 1999;10(Suppl 4):4–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Harizi H, Gualde N: Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators. Cell Mol Immunol 2006;3:271–277.PubMedGoogle Scholar
  8. 8.
    Zou W: Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 2005;5:263–274.CrossRefPubMedGoogle Scholar
  9. 9.
    Acuto O, Michel F: CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 2003;3:939–951.CrossRefPubMedGoogle Scholar
  10. 10.
    Alegre ML, Frauwirth KA, Thompson CB: T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001;1:220–228.CrossRefPubMedGoogle Scholar
  11. 11.
    Korman AJ, Peggs KS, Allison JP: Checkpoint blockade in cancer immunotherapy. Adv Immunol 2006;90:297–339.CrossRefPubMedGoogle Scholar
  12. 12.
    Chen L: Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004;4:336–347.CrossRefPubMedGoogle Scholar
  13. 13.
    Flies DB, Chen L: The new B7s: playing a pivotal role in tumor immunity. J Immunother 2007;30:251–260.CrossRefPubMedGoogle Scholar
  14. 14.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH: PD-1 and Its Ligands in Tolerance and Immunity. Annu Rev Immunol 2008;26:677–704.CrossRefPubMedGoogle Scholar
  15. 15.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T: Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319–322.CrossRefPubMedGoogle Scholar
  16. 16.
    Kryczek I, Wei S, Zou L, Zhu G, Mottram P, Xu H, Chen L, Zou W: Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 2006;177:40–44.PubMedGoogle Scholar
  17. 17.
    Shevach EM: Special regulatory T cell review: How I became a T suppressor/regulatory cell maven. Immunology 2008;123:3–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057–1061.CrossRefPubMedGoogle Scholar
  19. 19.
    Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S: Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002;3:135–142.CrossRefPubMedGoogle Scholar
  20. 20.
    McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC: CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16:311–323.CrossRefPubMedGoogle Scholar
  21. 21.
    Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, Collins M, Shevach EM: Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4 + CD25 + T cells. J Immunol 2004;173:5008–5020.PubMedGoogle Scholar
  22. 22.
    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA: Role of LAG-3 in regulatory T cells. Immunity 2004;21:503–513.CrossRefPubMedGoogle Scholar
  23. 23.
    Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, Anders R, Netto G, Getnet D, Bruno TC, Goldberg MV, Pardoll DM, Drake CG: LAG-3 regulates CD8 + T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest 2007;117:3383–3392.CrossRefPubMedGoogle Scholar
  24. 24.
    Maker AV, Attia P, Rosenberg SA: Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol 2005;175:7746–7754.PubMedGoogle Scholar
  25. 25.
    Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, Coukos G, Rubin SC, Kaiser LR, June CH: Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 2001;61:4766–4772.PubMedGoogle Scholar
  26. 26.
    Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ: Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 2001;194:823–832.CrossRefPubMedGoogle Scholar
  27. 27.
    Wang HY, Peng G, Guo Z, Shevach EM, Wang RF: Recognition of a new ARTC1 peptide ligand uniquely expressed in tumor cells by antigen-specific CD4 + regulatory T cells. J Immunol 2005;174:2661–2670.PubMedGoogle Scholar
  28. 28.
    Talmadge JE: Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res 2007;13:5243–5248.CrossRefPubMedGoogle Scholar
  29. 29.
    Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH: Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 2007;67:9518–9527.CrossRefPubMedGoogle Scholar
  30. 30.
    Katz JB, Muller AJ, Prendergast GC: Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev 2008;222:206–221.CrossRefPubMedGoogle Scholar
  31. 31.
    Bronte V, Zanovello P: Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5:641–654.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu XY, Pop LM, Vitetta ES: Engineering therapeutic monoclonal antibodies. Immunol Rev 2008;222:9–27.CrossRefPubMedGoogle Scholar
  33. 33.
    Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME: Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 2008;8:299–308.CrossRefPubMedGoogle Scholar
  34. 34.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850–854.CrossRefPubMedGoogle Scholar
  35. 35.
    Jaffee EM: Immunotherapy of cancer. Ann NY Acad Sci 1999;886:67–72.CrossRefPubMedGoogle Scholar
  36. 36.
    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 USA 1993;90:3539–3543.CrossRefPubMedGoogle Scholar
  37. 37.
    Simons JW, Jaffee EM, Weber CE, Levitsky HI, Nelson WG, Carducci MA, Lazenby AJ, Cohen LK, Finn CC, Clift SM, Hauda KM, Beck LA, Leiferman KM, Owens AH, Jr., Piantadosi S, Dranoff G, Mulligan RC, Pardoll DM, Marshall FF: Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res 1997;57:1537–1546.PubMedGoogle Scholar
  38. 38.
    Hege KM, Jooss K, Pardoll D: GM-CSF gene-modifed cancer cell immunotherapies: of mice and men. Int Rev Immunol 2006;25:321–352.CrossRefPubMedGoogle Scholar
  39. 39.
    Nemunaitis J: Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Expert Rev Vaccines 2005;4:259–274.CrossRefPubMedGoogle Scholar
  40. 40.
    Melief CJ, van der Burg SH: Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 2008;8:351–360.CrossRefPubMedGoogle Scholar
  41. 41.
    Singh R, Paterson Y: Listeria monocytogenes as a vector for tumor-associated antigens for cancer immunotherapy. Expert Rev Vaccines 2006;5:541–552.CrossRefPubMedGoogle Scholar
  42. 42.
    Singh R, Dominiecki ME, Jaffee EM, Paterson Y: Fusion to Listeriolysin O and delivery by Listeria monocytogenes enhances the immunogenicity of HER-2/neu and reveals subdominant epitopes in the FVB/N mouse. J Immunol 2005;175:3663–3673.PubMedGoogle Scholar
  43. 43.
    Brockstedt DG, Giedlin MA, Leong ML, Bahjat KS, Gao Y, Luckett W, Liu W, Cook DN, Portnoy DA, Dubensky TW, Jr: Listeria-based cancer vaccines that segregate immunogenicity from toxicity. Proc Natl Acad Sci USA 2004;101:13832–13837.CrossRefPubMedGoogle Scholar
  44. 44.
    Bruhn KW, Craft N, Nguyen BD, Yip J, Miller JF: Characterization of anti-self CD8 T-cell responses stimulated by recombinant Listeria monocytogenes expressing the melanoma antigen TRP-2. Vaccine 2005;23:4263–4272.CrossRefPubMedGoogle Scholar
  45. 45.
    Yoshimura K, Laird LS, Chia CY, Meckel KF, Slansky JE, Thompson JM, Jain A, Pardoll DM, Schulick RD: Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells. Cancer Res 2007;67:10058–10066.CrossRefPubMedGoogle Scholar
  46. 46.
    Brockstedt D, Leong M, Bahjat K, Liu W, Prell R, Lemmens E, Hanson B, Lauer P, Skoble J, Luckett W, Gao Y, Allen H, Jaffee E, Portnoy D, Pardoll D, Eiden J, Giedlin M, Dubensky T: Live-attenuated L. monocytogenes encoding mesothelin for immunotherapy of patients with pancreas and ovarian cancers. In AACR Meeting Abstracts 1874, 2007.Google Scholar
  47. 47.
    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;27:451–462.PubMedGoogle Scholar
  48. 48.
    Garnett CT, Greiner JW, Tsang KY, Kudo-Saito C, Grosenbach DW, Chakraborty M, Gulley JL, Arlen PM, Schlom J, Hodge JW: TRICOM vector based cancer vaccines. Curr Pharm Des 2006;12:351–361.CrossRefPubMedGoogle Scholar
  49. 49.
    Gilboa E: DC-based cancer vaccines. J Clin Invest 2007;117:1195–1203.CrossRefPubMedGoogle Scholar
  50. 50.
    Harzstark AL, Small EJ: Immunotherapy for prostate cancer using antigen-loaded antigen-presenting cells: APC8015 (Provenge). Expert Opin Biol Ther 2007;7:1275–1280.CrossRefPubMedGoogle Scholar
  51. 51.
    Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, Schmitt E, Hamai A, Hervas-Stubbs S, Obeid M, Coutant F, Metivier D, Pichard E, Aucouturier P, Pierron G, Garrido C, Zitvogel L, Kroemer G: Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005;202:1691–1701.CrossRefPubMedGoogle Scholar
  52. 52.
    Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, Okoye FI, Jaffee EM: Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 2001;61:3689–3697.PubMedGoogle Scholar
  53. 53.
    Chu Y, Wang LX, Yang G, Ross HJ, Urba WJ, Prell R, Jooss K, Xiong S, Hu HM: Efficacy of GM-CSF-producing tumor vaccine after docetaxel chemotherapy in mice bearing established Lewis lung carcinoma. J Immunother 2006;29:367–380.CrossRefPubMedGoogle Scholar
  54. 54.
    Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H: Inhibition of CD4(+)25 + T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005;105:2862–2868.CrossRefPubMedGoogle Scholar
  55. 55.
    Ercolini AM, Ladle BH, Manning EA, Pfannenstiel LW, Armstrong TD, Machiels JP, Bieler JG, Emens LA, Reilly RT, Jaffee EM: Recruitment of latent pools of high-avidity CD8(+) T cells to the antitumor immune response. J Exp Med 2005;201:1591–1602.CrossRefPubMedGoogle Scholar
  56. 56.
    Hermans IF, Chong TW, Palmowski MJ, Harris AL, Cerundolo V: Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res 2003;63:8408–8413.PubMedGoogle Scholar
  57. 57.
    Emens LA, Asquith JM, Leatherman JM, Daphtary MM, Petrik S, Fetting JH, Disis ML, Piantadosi S, Davidson NE, Jaffee EM, Increasing doses of cyclophosphamide suppress antigen-specific T helper-dependent immunity induced by a GM-CSF-secreting breast tumor vaccine. In ASCO Annual Meeting, 2008.Google Scholar
  58. 58.
    Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B: Metronomic cyclophosphamide regimen selectively depletes CD4 + CD25 + regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007;56:641–648.CrossRefPubMedGoogle Scholar
  59. 59.
    Tseng JF, Willett CG, Fernandez-del Castillo C, Ryan DP, Clark JW, Zhu AX, Rattner DW, Winkelmann JL, Warshaw AL: Patients undergoing treatment for pancreatic adenocarcinoma can mount an effective immune response to vaccinations. Pancreatology 2005;5:67–74.CrossRefPubMedGoogle Scholar
  60. 60.
    Ribas A, Hanson DC, Noe DA, Millham R, Guyot DJ, Bernstein SH, Canniff PC, Sharma A, Gomez-Navarro J: Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist 2007;12:873–883.CrossRefPubMedGoogle Scholar
  61. 61.
    Weber J: Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist 2007;12:864–872.CrossRefPubMedGoogle Scholar
  62. 62.
    Brahmer JR, Topalian S, Wollner I, Powderly JD, Picus J, Drake C, Covino J, Korman A, Pardoll D, Lowy I, Safety and activity of MDX-1106 (ONO-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies. In ASCO Annual Meeting, 2008.Google Scholar
  63. 63.
    Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, Nakamura S, Enomoto K, Yagita H, Azuma M, Nakajima Y: Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 2007;13:2151–2157.CrossRefPubMedGoogle Scholar
  64. 64.
    Goldberg MV, Maris CH, Hipkiss EL, Flies AS, Zhen L, Tuder RM, Grosso JF, Harris TJ, Getnet D, Whartenby KA, Brockstedt DG, Dubensky TW, Jr., Chen L, Pardoll DM, Drake CG: Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 2007;110:186–192.CrossRefPubMedGoogle Scholar
  65. 65.
    Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, Lyerly HK, Clay TM: Depletion of human regulatory T cells specifically enhances antigen specific immune responses to cancer vaccines. Blood 2008;112:610–618.CrossRefPubMedGoogle Scholar
  66. 66.
    Kindler HL, Niedzwiecki D, Hollis D, Oraefo E, Schrag D, Hurwitz H, McLeod HL, Mulcahy MF, Schilsky RL, Goldberg RM, Cancer and Leukemia Group B, A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB. In ASCO Annual Meeting, 2007.Google Scholar
  67. 67.
    Philip PA, Benedetti J, Fenoglio-Preiser C, Zalupski M, Lenz H, O’Reilly E, Wong R, Atkins J, Abruzzese J, Blanke C, Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. In ASCO Annual Meeting, 2007.Google Scholar
  68. 68.
    Vervenne W, Bennouna J, Humblet Y, Gill S, Moore MJ, Van Laethem J, Shang A, Cosaert J, Verslype C, Van Cutsem E, A randomized, double-blind, placebo (P) controlled, multicenter phase III trial to evaluate the efficacy and safety of adding bevacizumab (B) to erlotinib (E) and gemcitabine (G) in patients (pts) with metastatic pancreatic cancer. In ASCO Annual Meeting, 2008.Google Scholar
  69. 69.
    Small W, Mulcahy M, Benson A, Gold S, Bredesen R, Rademaker F, Talamonti M, A phase II trial of weekly gemcitabine and bevacizumab in combination with abdominal radiation therapy in patients with localized pancreatic cancer. In ASCO Annual Meeting, 2007.Google Scholar
  70. 70.
    Van Cutsem E, Lang I, D’haens G, Moiseyenko V, Zaluski J, Folprecht G, Tejpar S, Kisker O, Stroh C, Rougier P: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. In ASCO Annual Meeting, 2008.Google Scholar
  71. 71.
    Hassan R, Ebel W, Routhier EL, Patel R, Kline JB, Zhang J, Chao Q, Jacob S, Turchin H, Gibbs L, Phillips MD, Mudali S, Iacobuzio-Donahue C, Jaffee EM, Moreno M, Pastan I, Sass PM, Nicolaides NC, Grasso L: Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun 2007;7:20.PubMedGoogle Scholar
  72. 72.
    Reilly RT, Emens LA, Jaffee EM: Humoral and cellular immune responses: independent forces or collaborators in the fight against cancer? Curr Opin Investig Drugs 2001;2:133–135.PubMedGoogle Scholar
  73. 73.
    Wolpoe ME, Lutz ER, Ercolini AM, Murata S, Ivie SE, Garrett ES, Emens LA, Jaffee EM, Reilly RT: HER-2/neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8 + T cell effector function and tumor-free survival in Her-2/neu-transgenic mice. J Immunol 2003;171:2161–2169.PubMedGoogle Scholar
  74. 74.
    Kim PS, Armstrong TD, Song H, Wolpoe ME, Weiss V, Manning EA, Huang LQ, Murata S, Sgouros G, Emens LA, Reilly RT, Jaffee EM: Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest 2008;118:1700–1711.CrossRefPubMedGoogle Scholar
  75. 75.
    Kondo H, Hazama S, Kawaoka T, Yoshino S, Yoshida S, Tokuno K, Takashima M, Ueno T, Hinoda Y, Oka M: Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res 2008;28:379–387.PubMedGoogle Scholar
  76. 76.
    Gaudernack G: Prospects for vaccine therapy for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20:299–314.CrossRefPubMedGoogle Scholar
  77. 77.
    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.CrossRefPubMedGoogle Scholar
  78. 78.
    Gilliam AD, Topuzov EG, Garin AM, Pulay I, Broome P, Watson SA, Rowlands B, Takhar A, Beckingham I, Randomised, double blind, placebo-controlled, multi-centre, group-sequential trial of G17DT for patients with advanced pancreatic cancer unsuitable or unwilling to take chemotherapy. In ASCO Annual Meeting, 2004.Google Scholar
  79. 79.
    Shapiro J, Marshall J, Karasek P, Figer A, Oettle H, Couture F, Jeziorski K, Broome P, Hawkins R, G17DT + gemcitabine [Gem] versus placebo + Gem in untreated subjects with locally advanced, recurrent, or metastatic adenocarcinoma of the pancreas: Results of a randomized, double-blind, multinational, multicenter study. In ASCO Annual Meeting, 2005.Google Scholar
  80. 80.
    Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Soreide 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.CrossRefPubMedGoogle Scholar
  81. 81.
    Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, Eriksen JA, Moller M, Baksaas I, Lothe RA, Saeterdal I, Gaudernack G: 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;92:441–450.CrossRefPubMedGoogle Scholar
  82. 82.
    Toubaji A, Achtar M, Provenzano M, Herrin VE, Behrens R, Hamilton M, Bernstein S, Venzon D, Gause B, Marincola F, Khleif SN: Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother 2008;57:1413–1420.CrossRefPubMedGoogle Scholar
  83. 83.
    Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G: Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: A dose escalating phase I/II study. Br J Cancer 2006;95:1474–1482.CrossRefPubMedGoogle Scholar
  84. 84.
    Lepisto A, Geller B, McKolanis J, Ramanathan R, Finn O: Analysis of the immunological response to a MUC-1 loaded DC vaccine for human pancreatic cancer. In AACR Meeting Abstracts 4896, 2007.Google Scholar
  85. 85.
    Yanagmoto H, Satoi S, Mine T, Tanaka K, Yamada A, Oka M, Itoh K: A multicenter phase I/II study of gemcitabine and personalized peptide vaccination combination therapy for metastatic pancreatic cancer patients. In ASCO Annual Meeting, 2008.Google Scholar
  86. 86.
    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;52:1964–1972.CrossRefPubMedGoogle Scholar
  87. 87.
    Jaffee EM, Hruban RH, Biedrzycki B, Laheru D, Schepers K, Sauter PR, Goemann M, Coleman J, Grochow L, Donehower RC, Lillemoe KD, O’Reilly S, Abrams RA, Pardoll DM, Cameron JL, Yeo CJ: 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;19:145–156.PubMedGoogle Scholar
  88. 88.
    Laheru D, Yeo C, Biedrzycki B, Solt S, Lutz E, Onners B, Tartakovsky I, Herman J, Hruban R, Piantadosi S, Jaffee E, A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreas. In ASCO Annual Meeting, 2007.Google Scholar
  89. 89.
    Thomas AM, Santarsiero LM, Lutz ER, Armstrong TD, Chen YC, Huang LQ, Laheru DA, Goggins M, Hruban RH, Jaffee EM: Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 2004;200:297–306.CrossRefPubMedGoogle Scholar
  90. 90.
    Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, Tartakovsky I, Nemunaitis J, Le D, Sugar E, Hege K, Jaffee E: 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;14:1455–1463.CrossRefPubMedGoogle Scholar
  91. 91.
    Oyama Y, Talamonti M, Mulcahy M, Gonda E, Burt RK, Vahanian NN, Bell R, Tennant L, Ramsey WJ, Adrian T, Link C, A phase I/II study of an antitumor vaccination using α (1,3) galactosyltransferase expressing allogeneic tumor cells in pancreatic cancer. In ASCO Annual Meeting, 2007.Google Scholar
  92. 92.
    Zajchowski DA, Biroc SL, Liu HL, Chesney SK, Hoffmann J, Bauman J, Kirkland T, Subramanyam B, Shen J, Ho E, Tseng JL, Dinter H: Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl) cytosine (4′-thio-FAC) in human pancreatic and ovarian tumor xenograft models. Int J Cancer 2005;114:1002–1009.CrossRefPubMedGoogle Scholar
  93. 93.
    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;54:915–925.CrossRefPubMedGoogle Scholar
  94. 94.
    Brown ME, Miao H, McKee MD: Recognition of carcinoembryonic antigen peptide and heteroclitic peptide by peripheral blood T lymphocytes. J Immunother 2007;30:350–358.CrossRefPubMedGoogle Scholar
  95. 95.
    Argani P, Rosty C, Reiter RE, Wilentz RE, Murugesan SR, Leach SD, Ryu B, Skinner HG, Goggins M, Jaffee EM, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res 2001;61:4320–4324.PubMedGoogle Scholar
  96. 96.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL: CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543–9553.CrossRefPubMedGoogle Scholar
  97. 97.
    Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23:2346–2357.CrossRefPubMedGoogle Scholar
  98. 98.
    Embuscado EE, Laheru D, Ricci F, Yun KJ, de Boom Witzel S, Seigel A, Flickinger K, Hidalgo M, Bova GS, Iacobuzio-Donahue CA: Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy. Cancer Biol Ther 2005;4:548–554.CrossRefPubMedGoogle Scholar
  99. 99.
    Schlom J, Arlen PM, Gulley JL: Cancer vaccines: moving beyond current paradigms. Clin Cancer Res 2007;13:3776–3782.CrossRefPubMedGoogle Scholar
  100. 100.
    Hodi FS, Hoos A, Ibrahim R, Chin K, Pehamberger H, Harmankaya K, O’Day S, Hamid O, Humphrey R, Wolchok J, Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody. In ASCO Annual Meeting, 2008.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Lei Zheng
    • 1
  • Elizabeth M. Jaffee
    • 1
  1. 1.The Sidney Kimmel Cancer Center at Johns Hopkins Bunting-Blaustein Cancer ResearchBaltimoreUSA

Personalised recommendations