title: Anti-IL-23 monoclonal antibody synergizes in combination with targeted therapies or IL-2 to suppress tumor growth and metastases.
abstract: Immunosuppressive barricades erected by tumors during the evolution of immune escape represent a major obstacle to many potentially effective cancer therapies and vaccines. We have shown that host interleukin (IL)-23 suppresses the innate immune response during carcinogenesis and metastasis, independently of effects on the proinflammatory cytokine IL-17A. Based on these findings, we envisioned that IL-23 neutralization might offer a promising strategy to modulate immunosuppression, particularly in combination with immunostimulatory agents. Here we show that by itself a neutralizing monoclonal antibody (mAb) to IL-23 suppressed early experimental lung metastases in the B16F10 mouse model of melanoma and also modestly inhibited the subcutaneous growth of primary tumors. These antitumor effects were respectively mediated by natural killer cells or CD8(+) T cells. More notably, combinatorial treatments of anti-IL-23 mAb with IL-2 or anti-erbB2 mAb significantly inhibited subcutaneous growth of established mammary carcinomas and suppressed established experimental and spontaneous lung metastases. Overall, our results suggest the potential of anti-human IL-23 mAbs to improve the immunostimulatory effects of IL-2 and trastuzumab in the current management of some advanced human cancers.
authors.affiliation: Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Melbourne, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Bianca
authors.initials: B
authors.lastname: von Scheidt
authors.forename: Helene
authors.initials: H
authors.lastname: Duret
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Towne
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D053759:Interleukin-23; D018719:Erb-b2 Receptor Tyrosine Kinases