title: Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
abstract: Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.
authors.affiliation: National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley WA, Australia.
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Lesterhuis
authors.forename: Joanne
authors.initials: J
authors.lastname: Salmons
authors.forename: Anna K
authors.initials: AK
authors.lastname: Nowak
authors.forename: Esdy N
authors.initials: EN
authors.lastname: Rozali
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.forename: Ian M
authors.initials: IM
authors.lastname: Dick
authors.forename: Julie A
authors.initials: JA
authors.lastname: Harken
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Robinson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007113:Immunity, Innate / Q000187:drug effects*; D007155:Immunologic Factors / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008212:Lymphocyte Depletion; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D003841:Deoxycytidine; D000093542:Gemcitabine