title: Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses.
abstract: Oncolytic reovirus can be delivered both systemically and intratumorally, in both preclinical models and in early phase clinical trials. Reovirus has direct oncolytic activity against a variety of tumor types and antitumor activity is directly associated with immune activation by virus replication in tumors. Immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, and the generation of adaptive antitumor immune responses as a result of in vivo priming against tumor-associated antigens. We tested the combination of local oncolytic reovirus therapy with systemic immune checkpoint inhibition. We show that treatment of subcutaneous B16 melanomas with a combination of intravenous (i.v.) anti-PD-1 antibody and intratumoral (i.t.) reovirus significantly enhanced survival of mice compared to i.t. reovirus (P < 0.01) or anti-PD-1 therapy alone. In vitro immune analysis demonstrated that checkpoint inhibition improved the ability of NK cells to kill reovirus-infected tumor cells, reduced T(reg) activity, and increased the adaptive CD8(+) T-cell-dependent antitumor T-cell response. PD-1 blockade also enhanced the antiviral immune response but through effector mechanisms which overlapped with but also differed from those affecting the antitumor response. Therefore, combination with checkpoint inhibition represents a readily translatable next step in the clinical development of reovirus viroimmunotherapy.
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Karishma
authors: K
authors: Rajani
authors: Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK.
authors: Christopher
authors: C
authors: Parrish
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Timothy
authors: T
authors: Kottke
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Jill
authors: J
authors: Thompson
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Shane
authors: S
authors: Zaidi
authors: Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK.
authors: Liz
authors: L
authors: Ilett
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Kevin G
authors: KG
authors: Shim
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Rosa-Maria
authors: RM
authors: Diaz
authors: University of Surrey, Guildford, UK.
authors: Hardev
authors: H
authors: Pandha
authors: The Institute of Cancer Research, London, UK.
authors: Kevin
authors: K
authors: Harrington
authors: Oncolytics Biotech Incorporated, Calgary, Alberta, Canada.
authors: Matt
authors: M
authors: Coffey
authors: Cancer Research UK Clinical Centre, St. James' University Hospital, Leeds, UK.
authors: Alan
authors: A
authors: Melcher
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.|Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Richard
authors: R
authors: Vile
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D007113:Immunity, Innate; D008546:Melanoma, Experimental / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D012087:Reoviridae / Q000502:physiology*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D061026:Programmed Cell Death 1 Receptor