Anti-CD40/Anti-CD40L

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Abstract

CD40 receptor and its ligand CD40L have a multifactorial role in inflammation, angiogenesis, and tumor modulation. High levels of soluble CD40L alone are associated with increased angiogenesis and systemic inflammation. High levels of the ligand alone are also associated with poorer tumor outcomes. However, increased levels of both the ligand and receptor are associated with increased tumor antigen presentation by antigen presenting cells and have an antitumor effect. The combination of receptor stimulation with agonist antibody and IL-2 has been shown to potentiate antitumor effect, increase NK cell activity against tumors, and delete regulatory T cells. In clinical trials with agonist antibody alone, there was a modest effect with patients with melanoma having the best outcomes, with a minority of patients having some responses. Cytokine release syndrome was the most common adverse event. Rational combinations of cytokines with the use of novel immunotherapies targeting CD40 may show promise in the treatment of neoplastic disease.

Keywords

Chronic Lymphocytic Leukemia CD40 Ligand Chronic Lymphocytic Leukemia Cell Borderline Ovarian Tumor Cytokine Release Syndrome 
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.
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References

  1. Advani R, Forero-Torres A, Furman RR, et al. Phase I study of the humanized anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27(26):4371–7.CrossRefPubMedGoogle Scholar
  2. Aloui C, Prigent A, Sut C, et al. The signaling role of CD40 ligand in platelet biology and in platelet component transfusion. Int J Mol Sci. 2014;15(12):22342–64.CrossRefPubMedGoogle Scholar
  3. Beatty GL, Torigian DA, Chiorean EG, et al. A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Clin Cancer Res. 2013;19(22):6286–95.CrossRefPubMedGoogle Scholar
  4. Bensinger W, Maziarz RT, Jagannath S, et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol. 2012;159(1):58–66.CrossRefPubMedGoogle Scholar
  5. Bransi A, Salgado OC, Beffinger M, et al. Rational combination of immunotherapies with clinical efficacy in mice with advanced cancer. Cancer Immunol Res. 2015;3(11):1279–88.CrossRefPubMedGoogle Scholar
  6. Bussolati B, Russo S, Deambrosis I, et al. Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet-activating factor synthesis. Int J Cancer. 2002;100(6):654–61.CrossRefPubMedGoogle Scholar
  7. Byrd JC, Kipps TJ, Flinn IW, et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(11):2136–42.CrossRefPubMedGoogle Scholar
  8. Byrne KT, Vonderheide RH. CD40 stimulation obviates innate sensors and drives t cell immunity in cancer. Cell Rep. 2016;15(12):2719–32.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Carlring J, Szabo MJ, Dickinson R, De Leenheer E, Heath AW. Conjugation of lymphoma idiotype to CD40 antibody enhances lymphoma vaccine immunogenicity and antitumor effects in mice. Blood. 2012;119(9):2056–65.CrossRefPubMedGoogle Scholar
  10. Castro JE, Melo-Cardenas J, Urquiza M, Barajas-Gamboa JS, Pakbaz RS, Kipps TJ. Gene immunotherapy of chronic lymphocytic leukemia: a phase I study of intranodally injected adenovirus expressing a chimeric CD154 molecule. Cancer Res. 2012;72(12):2937–48.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chen L, Park SM, Tumanov AV, et al. CD95 promotes tumour growth. Nature. 2010;465(7297):492–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Chonan M, Saito R, Shoji T, et al. CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models. Neuro Oncol. 2015;17(11):1453–62.CrossRefPubMedPubMedCentralGoogle Scholar
  13. El Fakhry Y, Alturaihi H, Yacoub D, et al. Functional interaction of CD154 protein with alpha5beta1 integrin is totally independent from its binding to alphaIIbbeta3 integrin and CD40 molecules. J Biol Chem. 2012;287(22):18055–66.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Eliopoulos AG, Davies C, Knox PG, et al. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol. 2000;20(15):5503–15.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Furman RR, Forero-Torres A, Shustov A, Drachman JG. A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2010;51(2):228–35.CrossRefPubMedGoogle Scholar
  16. Hassan GS, Stagg J, Mourad W. Role of CD154 in cancer pathogenesis and immunotherapy. Cancer Treat Rev. 2015;41(5):431–40.CrossRefPubMedGoogle Scholar
  17. Hooren LV, Georganaki M, Huang H, Mangsbo SM, Dimberg A. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment. Oncotarget. 2016.Google Scholar
  18. Hussein M, Berenson JR, Niesvizky R, et al. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica. 2010;95(5):845–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Jackaman C, Nelson DJ. Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ −independent resolution of treated-tumors and CD4+ −dependent systemic and memory responses. Cancer Immunol Immunother. 2012;61(4):549–60.CrossRefPubMedGoogle Scholar
  20. Jackaman C, Lansley S, Allan JE, Robinson BW, Nelson DJ. IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase. Int Immunol. 2012;24(6):357–68.CrossRefPubMedGoogle Scholar
  21. Jak M, van Bochove GG, Reits EA, et al. CD40 stimulation sensitizes CLL cells to lysosomal cell death induction by type II anti-CD20 mAb GA101. Blood. 2011;118(19):5178–88.CrossRefPubMedGoogle Scholar
  22. Kerkar SP, Leonardi AJ, van Panhuys N, et al. Collapse of the tumor stroma is triggered by IL-12 induction of Fas. Mol Ther. 2013;21(7):1369–77.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Klebanoff CA, Scott CD, Leonardi AJ, et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J Clin Invest. 2016;126(1):318–34.CrossRefPubMedGoogle Scholar
  24. Kwong B, Liu H, Irvine DJ. Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy. Biomaterials. 2011;32(22):5134–47.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Luheshi NM, Coates-Ulrichsen J, Harper J, et al. Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. Oncotarget. 2016;7(14):18508–20.PubMedPubMedCentralGoogle Scholar
  26. Matthies KM, Newman JL, Hodzic A, Wingett DG. Differential regulation of soluble and membrane CD40L proteins in T cells. Cell Immunol. 2006;241(1):47–58.CrossRefPubMedGoogle Scholar
  27. Okur FV, Yvon E, Biagi E, et al. Comparison of two CD40-ligand/interleukin-2 vaccines in patients with chronic lymphocytic leukemia. Cytotherapy. 2011;13(9):1128–39.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Pesonen S, Diaconu I, Kangasniemi L, et al. Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients. Cancer Res. 2012;72(7):1621–31.CrossRefPubMedGoogle Scholar
  29. Ruter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther. 2010;10(10):983–93.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Tutt AL, O’Brien L, Hussain A, Crowther GR, French RR, Glennie MJ. T cell immunity to lymphoma following treatment with anti-CD40 monoclonal antibody. J Immunol. 2002;168(6):2720–8.CrossRefPubMedGoogle Scholar
  31. van den Oord JJ, Maes A, Stas M, et al. CD40 is a prognostic marker in primary cutaneous malignant melanoma. Am J Pathol. 1996;149(6):1953–61.PubMedPubMedCentralGoogle Scholar
  32. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19(5):1035–43.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Vonderheide RH, Dutcher JP, Anderson JE, et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001;19(13):3280–7.PubMedGoogle Scholar
  34. Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25(7):876–83.CrossRefPubMedGoogle Scholar
  35. Vonderheide RH, Burg JM, Mick R, et al. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology. 2013;2(1):e23033.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Weiss JM, Wiltout RH. Multifaceted antitumor responses to activating anti-CD40 antibody therapy combined with immunomodulatory or targeted agents. Oncoimmunology. 2014;3(8):e954483.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Wierda WG, Castro JE, Aguillon R, et al. A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154. Leukemia. 2010;24(11):1893–900.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Zippelius A, Schreiner J, Herzig P, Muller P. Induced PD-L1 expression mediates acquired resistance to agonistic anti-CD40 treatment. Cancer Immunol Res. 2015;3(3):236–44.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, New York (outside the USA) 2016

Authors and Affiliations

  1. 1.Medical Oncology Service, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.St. George’s Medical SchoolUniversity of LondonLondonUK

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