title: CD1d-based combination therapy eradicates established tumors in mice.
abstract: The use of Abs that induce tumor cell death together with immunostimulatory reagents to activate innate and adaptive immune cells has emerged as a potent approach for the treatment of cancer. We have previously demonstrated that the use of three mAbs (anti-DR5, anti-CD40, anti-CD137) termed TriMab can induce rejection in a majority of mice with established experimental or carcinogen-induced tumors. However, given the potential toxicity of CD40 agonists in the clinic, we tested an alternative approach to directly activate/mature APCs using anti-CD1d mAbs. In this study, we used a combination of three mAbs (anti-DR5, anti-CD137, anti-CD1d) that we termed 1DMab and demonstrated that this approach suppressed and/or eradicated established experimental renal, breast, and colon carcinomas in mice. Tumor suppression induced by 1DMab therapy required CD8(+) T cells, IFN-gamma, and CD1d, while NK cells and IL-12 were partially required. Interestingly 1DMab therapy was more effective than TriMab in tumor models regulated by CD1d-restricted type II NKT cells, but less efficacious against tumors where T regulatory cells were critical. Anti-CD1d mAbs could also be relatively effective in combination with anti-CD137 and conventional chemotherapeutics. This is the first study to illustrate the antitumor activity of CD1d-reactive mAbs in combination and our results strongly suggest that rational combination chemoimmunotherapies based on tumor immunoregulation may improve the efficacy of treatment.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.forename: Janelle
authors.initials: J
authors.lastname: Sharkey
authors.forename: Nicole M
authors.initials: NM
authors.lastname: McLaughlin
authors.forename: Mark A
authors.initials: MA
authors.lastname: Exley
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000187:drug effects*; D055610:Antigens, CD1d / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D055610:Antigens, CD1d; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9