Cancer Immunology, Immunotherapy

, Volume 62, Issue 5, pp 949–954 | Cite as

CD40 immunotherapy for pancreatic cancer

  • Robert H. Vonderheide
  • David L. Bajor
  • Rafael Winograd
  • Rebecca A. Evans
  • Lauren J. Bayne
  • Gregory L. Beatty
Focussed Research Review

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, we describe both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, supporting the concept that immune modulation of the tumor microenvironment represents a useful approach in cancer immunotherapy.

Keywords

Tumor immunity CD40 Pancreatic cancer Macrophages T cells CIMT 2012 

References

  1. 1.
    Vonderheide RH (2007) Prospect of targeting the CD40 pathway for cancer therapy. Clin Cancer Res 13(4):1083–1088PubMedCrossRefGoogle Scholar
  2. 2.
    Grewal IS, Flavell RA (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16:111–135PubMedCrossRefGoogle Scholar
  3. 3.
    van Kooten C, Banchereau J (2000) CD40–CD40 ligand. J Leukoc Biol 67(1):2–17PubMedGoogle Scholar
  4. 4.
    Lanzavecchia A (1998) Immunology. Licence to kill. Nature 393(6684):413–414PubMedCrossRefGoogle Scholar
  5. 5.
    Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR et al (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357:80–82PubMedCrossRefGoogle Scholar
  6. 6.
    Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ (2004) CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307–328PubMedCrossRefGoogle Scholar
  7. 7.
    Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393(6684):478–480PubMedCrossRefGoogle Scholar
  8. 8.
    Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4 + T-helper and a T-killer cell. Nature 393(6684):474–478PubMedCrossRefGoogle Scholar
  9. 9.
    Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393(6684):480–483PubMedCrossRefGoogle Scholar
  10. 10.
    French RR, Chan HT, Tutt AL, Glennie MJ (1999) CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med 5(5):548–553PubMedCrossRefGoogle Scholar
  11. 11.
    Diehl L, den Boer AT, Schoenberger SP, van der Voort EI, Schumacher TN, Melief CJ, Offringa R, Toes RE (1999) CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 5(7):774–779PubMedCrossRefGoogle Scholar
  12. 12.
    Sotomayor EM, Borrello I, Tubb E, Rattis FM, Bien H, Lu Z, Fein S, Schoenberger S, Levitsky HI (1999) Conversion of tumor-specific CD4 + T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med 5(7):780–787PubMedCrossRefGoogle Scholar
  13. 13.
    Nowak AK, Robinson BW, Lake RA (2003) Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 63(15):4490–4496PubMedGoogle Scholar
  14. 14.
    Ahonen CL, Doxsee CL, McGurran SM, Riter TR, Wade WF, Barth RJ, Vasilakos JP, Noelle RJ, Kedl RM (2004) Combined TLR and CD40 triggering induces potent CD8 + T cell expansion with variable dependence on type I IFN. J Exp Med 199(6):775–784PubMedCrossRefGoogle Scholar
  15. 15.
    Tong AW, Papayoti MH, Netto G, Armstrong DT, Ordonez G, Lawson JM, Stone MJ (2001) Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res 7(3):691–703PubMedGoogle Scholar
  16. 16.
    Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, Gejyo F, Okumura K, Yagita H, Smyth MJ (2006) Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med 12(6):693–698PubMedCrossRefGoogle Scholar
  17. 17.
    Ahonen CL, Wasiuk A, Fuse S, Turk MJ, Ernstoff MS, Suriawinata AA, Gorham JD, Kedl RM, Usherwood EJ, Noelle RJ (2008) Enhanced efficacy and reduced toxicity of multifactorial adjuvants compared with unitary adjuvants as cancer vaccines. Blood 111(6):3116–3125PubMedCrossRefGoogle Scholar
  18. 18.
    Vonderheide RH, Glennie MJ (2013) Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res 19(5):1035–1043PubMedCrossRefGoogle Scholar
  19. 19.
    Gladue RP, Paradis T, Cole SH, Donovan C, Nelson R, Alpert R, Gardner J, Natoli E, Elliott E, Shepard R, Bedian V (2011) The CD40 agonist antibody CP-870,893 enhances dendritic cell and B-cell activity and promotes anti-tumor efficacy in SCID-hu mice. Cancer Immunol Immunother 60(7):1009–1017PubMedCrossRefGoogle Scholar
  20. 20.
    Carpenter EL, Mick R, Ruter J, Vonderheide RH (2009) Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous toll-like receptor 9 stimulation. J Transl Med 7:93PubMedCrossRefGoogle Scholar
  21. 21.
    Hunter TB, Alsarraj M, Gladue RP, Bedian V, Antonia SJ (2007) An agonist antibody specific for CD40 induces dendritic cell maturation and promotes autologous anti-tumour T-cell responses in an in vitro mixed autologous tumour cell/lymph node cell model. Scand J Immunol 65(5):479–486PubMedCrossRefGoogle Scholar
  22. 22.
    Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, Sullivan P, Mahany JJ, Gallagher M, Kramer A, Green SJ, O’Dwyer PJ, Running KL, Huhn RD, Antonia SJ (2007) Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 25(7):876–883PubMedCrossRefGoogle Scholar
  23. 23.
    Ruter J, Antonia SJ, Burris HA 3rd, Huhn RD, Vonderheide RH (2010) Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther 10(10):983–993PubMedCrossRefGoogle Scholar
  24. 24.
    Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O’Dwyer PJ, Vonderheide RH (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331(6024):1612–1616PubMedCrossRefGoogle Scholar
  25. 25.
    Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, Tolcher AW, Hamid O (2013) Phase I study of CD40 antibody CP-870,893 in combination with carboplatin and paclitaxel in patients with advanced solid tumors. OncoImmunology 2(1):e23033Google Scholar
  26. 26.
    Bergmann S, Pandolfi PP (2006) Giving blood: a new role for CD40 in tumorigenesis. J Exp Med 203(11):2409–2412PubMedCrossRefGoogle Scholar
  27. 27.
    Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren H, Harrop K, Whiting N, Drachman JG (2009) Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol 27(26):4371–4377PubMedCrossRefGoogle Scholar
  28. 28.
    Fransen MF, Sluijter M, Morreau H, Arens R, Melief CJ (2011) Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody. Clin Cancer Res 17(8):2270–2280PubMedCrossRefGoogle Scholar
  29. 29.
    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 (2001) 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 19(1):145–156PubMedGoogle Scholar
  30. 30.
    Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, Sugar E, Piantadosi S, Cameron JL, Solt S, Onners B, Tartakovsky I, Choi M, Sharma R, Illei PB, Hruban RH, Abrams RA, Le D, Jaffee E, Laheru D (2011) 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 253(2):328–335PubMedCrossRefGoogle Scholar
  31. 31.
    Plate JM (2012) Advances in therapeutic vaccines for pancreatic cancer. Discov Med 14(75):89–95PubMedGoogle Scholar
  32. 32.
    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413PubMedGoogle Scholar
  33. 33.
    Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7(5):469–483PubMedCrossRefGoogle Scholar
  34. 34.
    Clark CE, Beatty GL, Vonderheide RH (2009) Immunosurveillance of pancreatic adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer Lett 279(1):1–7PubMedCrossRefGoogle Scholar
  35. 35.
    Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH (2007) Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res 67(19):9518–9527PubMedCrossRefGoogle Scholar
  36. 36.
    Buhtoiarov IN, Lum H, Berke G, Paulnock DM, Sondel PM, Rakhmilevich AL (2005) CD40 ligation activates murine macrophages via an IFN-gamma-dependent mechanism resulting in tumor cell destruction in vitro. J Immunol 174(10):6013–6022PubMedGoogle Scholar
  37. 37.
    Rakhmilevich AL, Buhtoiarov IN, Malkovsky M, Sondel PM (2008) CD40 ligation in vivo can induce T cell independent antitumor effects even against immunogenic tumors. Cancer Immunol Immunother 57(8):1151–1160PubMedCrossRefGoogle Scholar
  38. 38.
    O’Sullivan T, Saddawi-Konefka R, Vermi W, Koebel CM, Arthur C, White JM, Uppaluri R, Andrews DM, Ngiow SF, Teng MW, Smyth MJ, Schreiber RD, Bui JD (2012) Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med 209(10):1869–1882PubMedCrossRefGoogle Scholar
  39. 39.
    Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355):222–225PubMedCrossRefGoogle Scholar
  40. 40.
    DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA, Rugo HS, Hwang ES, Jirstrom K, West BL, Coussens LM (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67PubMedCrossRefGoogle Scholar
  41. 41.
    Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237PubMedCrossRefGoogle Scholar
  42. 42.
    Bayne LJ, Beatty GL, Jhala N, Clark CE, Rhim AD, Stanger BZ, Vonderheide RH (2012) Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21(6):822–835PubMedCrossRefGoogle Scholar
  43. 43.
    Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21(6):836–847PubMedCrossRefGoogle Scholar
  44. 44.
    Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT (2011) Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330(6005):827–830CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Robert H. Vonderheide
    • 1
    • 2
  • David L. Bajor
    • 1
    • 2
  • Rafael Winograd
    • 1
  • Rebecca A. Evans
    • 1
  • Lauren J. Bayne
    • 1
  • Gregory L. Beatty
    • 2
  1. 1.Abramson Family Cancer Research Institute, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Division of Hematology-Oncology, Department of Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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