title: Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice.
abstract: Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.
authors: *Section of Surgical Oncology, University of Wisconsin School of Medicine and Public Health †Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine ‡Surgical Service, William S. Middleton Memorial VA Hospital, Madison, WI.
authors: David A
authors: DA
authors: Mahvi
authors: Justin V
authors: JV
authors: Meyers
authors: Andrew J
authors: AJ
authors: Tatar
authors: Amanda
authors: A
authors: Contreras
authors: Marulasiddappa
authors: M
authors: Suresh
authors: Glen E
authors: GE
authors: Leverson
authors: Siddhartha
authors: S
authors: Sen
authors: Clifford S
authors: CS
authors: Cho
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D016219:Immunotherapy, Adoptive; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D047368:Tumor Burden; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D060908:CTLA-4 Antigen; D006023:Glycoproteins; D010446:Peptide Fragments; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus