Abstract A14: Checkpoinblockade enhances oncolytic herpes virotherapy in immunosuppressive sarcoma models

Most solid tumors are characterized by an immunosuppressive microenvironment, limiting the effectiveness of antitumor immunotherapeutics. Programmed cell death protein (PD)-1-mediated T cell suppression via engagement of its ligand, PD-L1, is of particular interest due to recent successes in selected adult cancers. The utility of PD1-directed therapy for pediatric cancers is unknown, especially given the paucity of mutations and thus infrequent neoantigens in many types of childhood tumors. Oncolytic virotherapy induces tumor shrinkage via a multistep process including direct tumor cell lysis, induction of cytotoxic or apoptosis-sensitizing cytokines, and induction of anti-tumor T cell responses. We recently demonstrated that intratumoral injection of an oncolytic herpes virus induced growth delays and in some cases durable remissions in several mouse models of rhabdomyosarcoma. The effects were T cell mediated, rendering surviving mice resistant to tumor rechallenge and being absent in athymic nude hosts (Leddon et al., Mol Ther-Oncolytics 1, Article number: 14010, 2015). We found these tumor models express PD-L1, suggesting that T cell checkpoints may in part limit virus-induced antitumor immunity. Here we show the implantable C57Bl/6 rhabdomyosarcoma model, M3-9-M, showed a moderate response to single-agent Seprehvir (HSV1716), a virus currently in pediatric clinical trials (NCT00931931, NCT02031965). Single-agent PD-1 blockade also showed moderate but significant tumor growth delay with no complete responses. Strikingly, combining these two therapies together substantially prolonged overall survival with several complete responses post 40 days treatment. We hypothesize that virotherapy-induced chemokine secretion increases the recruitment of antitumor T cells, while PD-1 blockade increases their effectiveness. Overall, our data suggest the combination of PD-1 and oncolytic herpes virotherapy may be an effective treatment strategy for some cancers. Citation Format: Chun-yu Chun, Pin-Yi Wang, Brian Hutzen, Kellie Haworth, Joe Conner, Timothy Cripe. Checkpoinblockade enhances oncolytic herpes virotherapy in immunosuppressive sarcoma models. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A14.