title: Combined anti-CD40 and anti-IL-23 monoclonal antibody therapy effectively suppresses tumor growth and metastases.
abstract: Tumor-induced immunosuppression remains one of the major obstacles to many potentially effective cancer therapies and vaccines. Host interleukin (IL)-23 suppresses the immune response during tumor initiation, growth, and metastases, and neutralization of IL-23 causes IL-12-dependent antitumor effects. Here, we report that combining agonistic anti-CD40 monoclonal antibodies (mAb) to drive IL-12 production and anti-IL-23 mAbs to counter the tumor promoting effects of IL-23 has greater antitumor activity than either agent alone. This increased antitumor efficacy was observed in several experimental and spontaneous lung metastases models as well as in models of de novo carcinogenesis. The combination effects were dependent on host IL-12, perforin, IFN-γ, natural killer, and/or T cells and independent of host B cells and IFN-αβ sensitivity. Interestingly, in the experimental lung metastases tumor models, we observed that intracellular IL-23 production was specifically restricted to MHC-II(hi)CD11c(+)CD11b(+) cells. Furthermore, an increase in proportion of these IL-23-producing cells was detected only in tumor models where IL-23 neutralization was therapeutic. Overall, these data suggest the clinical potential of using anti-CD40 (push) and anti-IL-23 mAbs (pull) to tip the IL-12/23 balance in established tumors.
authors.affiliation: Authors' Affiliations: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria; Immunology in Cancer and Infection Laboratory; Cancer Immunoregulation and Immunotherapy Laboratory, Queensland Institute of Medical Research; School of Medicine, University of Queensland, Herston, Queensland, Australia; and AMGEN Incorporated, Seattle, Washington.
authors.forename: Bianca
authors.initials: B
authors.lastname: von Scheidt
authors.forename: Patrick S K
authors.initials: PS
authors.lastname: Leung
authors.forename: Michelle C R
authors.initials: MC
authors.lastname: Yong
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Towne
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D019013:CD40 Antigens / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy; D018664:Interleukin-12 / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D053759:Interleukin-23; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D018664:Interleukin-12; D008748:Methylcholanthrene