Abstract A070: Virotherapy eradicates established melanoma by reprogramming the tumor microenvironment and engaging the adaptive immunity

Abstract

Immunotherapy revolutionized the treatment of cancer patients. However, the lack of tumor specific T-cells and the immunosuppressive tumor microenvironment remain the major obstacles in curing treatment-resistant tumors. Here, we show that a novel, propagating noncytopathic virotherapy expressing the tumor-associated antigen TRP2 can eradicate established tumors. Interestingly, this was dependent on the route of treatment. Systemic administration of gene-based virotherapy induced a high number of tumor-infiltrating TRP2 specific CD8+ T-cells but was not able to cure established tumors. Moreover, localized tumor therapy in the periphery cured also distant metastasis in the lung, indicating that the locally induced immune response generates a systemic antitumor effect. Localized virotherapy predominantly infects tumor cells and tumor-associated fibroblasts, resulting in a proinflammatory reprogramming of the tumor microenvironment. Our data reveal that this immune activation is dependent on type I IFN signaling on the host but not on the tumor cell. These results have important clinical implications: i) our data explain why T-cell transfer or T-cell vaccines alone do not cure established tumors; ii) intratumoral gene-based cancer vaccination is superior to systemic treatment; and iii) a successful local antitumor response is associated with an efficient systemic antitumor response. Directly cancer targeting noncytopathic gene-based vaccines may be a promising approach by simultaneously supercharging the suppressive tumor microenvironment and inducing an adaptive immune response against selected tumor antigens. Citation Format: Lukas Flatz, Sandra Ring, David Bomze, Lucas Onder, Jovana Cupovic, Sarah Schmidt, Klaus Orlinger, Andrej Besse, Lenka Besse, Christoph Driessen, Hung-Wei Cheng, Alexander Lercher, Daniel Speiser, Tobias Bald, Andreas Bergthaler, Burkhard Ludewig. Virotherapy eradicates established melanoma by reprogramming the tumor microenvironment and engaging the adaptive immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A070.