Abstract 2219: OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models

Abstract

Abstract Inhibition of the immune-checkpoint axis that involves PD-L1/PD-1 has improved responses and outcomes for certain cancer patients, but there remains unmet need as only a fraction of patients respond to these therapies. Talimogene laherparepvec (T-VEC) is an FDA-approved, first-in-class oncolytic immunotherapy based on a modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate in tumors and produce granulocyte-macrophage stimulating factor (GM-CSF) to enhance a tumor-antigen specific adaptive immune response. Intratumoral treatment with T-VEC has been shown to promote an inflammatory tumor microenvironment both preclinically and clinically. Combining T-VEC with immune checkpoint inhibitors is of high interest to potentially broaden and deepen the clinical responses in checkpoint-resistant tumors. In the current study, we evaluated the efficacy of OncoVEXmGM-CSF (an HSV modified like T-VEC, except that it produces murine GM-CSF) in combination with anti-PD-1/PD-L1 treatment in multiple syngeneic mouse tumor models. Bilateral tumor models were used, where only one tumor was treated with OncoVEXmGM-CSF (representing the local oncolytic effect), allowing the evaluation of systemic abscopal effect in the uninjected contralateral tumors. OncoVEXmGM-CSF in combination with anti-PD-L1/PD-1 enhanced tumor growth inhibition in both treated and contralateral tumors in the A20 and MC38 syngeneic models and overcame anti-PD-L1 resistance in the CT26 model. The combination treatment also led to a significant increase in median overall survival compared to either agent as a monotherapy. In addition, tumor antigen epitopes were identified by combining exome sequencing and MHC/HLA-binding prediction algorithms. Antigen-specific T cell response was measured in an IFN-γ ELISPOT assay using splenocytes from treated mice. OncoVEXmGM-CSF induced and /or enhanced systemic T cell responses directed against both tumor neoantigens and tumor-associated antigens. Together, these data reveal that OncoVEXmGM-CSF treatment can cause direct tumor lysis along with the potentiation of an adaptive, systemic T cell-mediated anti-tumor immune response that can be enhanced by the addition of PD-L1/PD-1. Our study provides a strong rationale for the ongoing clinical evaluation of the combination of T-VEC and PD1-/PD-L1-targeted therapy in cancer patients. Citation Format: Keegan Cooke, Juan Estrada, Petia Mitchell, Jinghiu Zhan, Pedro J. Beltran, Jing Qing, Jude Canon. OnxoVEXmGM-CSF promotes systemic response to PD-L1 /PD-1 blockade in multiple mouse syngeneic tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2219.