Abstract A08: TGFβb Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

Abstract Oncolytic viruses are an emerging class of cancer therapeutics that couple cytotoxicity with the induction of an antitumor immune response. Host-virus interactions are complex and modulated by a tumor microenvironment whose immunosuppressive activities can limit the effectiveness of cancer immunotherapies. In an effort to improve this aspect of oncolytic virotherapy, we combined the oncolytic herpes virus HSV1716 with the TGFβR1 inhibitor A8301 to treat syngeneic models of murine rhabdomyosarcoma. Mice that received HSV1716 or A8301 alone showed little to no benefit in efficacy/survival over controls. Conversely, mice given combination therapy exhibited tumor stabilization throughout the treatment regimen, which was reflected in significantly prolonged survival times including some complete responses. In vitro cell viability and virus replication assays showed that the rhabdomyosarcoma cell lines were generally insensitive to HSV1716 and A8301. Likewise, in vivo virus replication assays showed that HSV1716 titers moderately decreased in the presence of A8301. The enhanced efficacy instead appears to be dependent on the generation of an improved antitumor T-cell response as determined by its loss in athymic nude mice and following in vivo depletion of either CD4+ or CD8+ cells. These data suggest that TGFβ inhibition can augment the immunotherapeutic efficacy of oncolytic herpes virotherapy. Citation Format: Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Swain M. Hayley, Julia Love, Joe Conner, Louis Boon, Timothy P. Cripe. TGFβb inhibition improves oncolytic herpes viroimmunotherapy in murine models of rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A08.