Optimized arenavirus vectors with tumor-tropic mutations as new class of amplificators of anti-tumoral T cell responses 2259607

Abstract

Abstract Introduction Recent understandings of anti-tumoral immune mechanisms reveal a critical role for strong and sustainable activation of CD8+ T cells for successful immunotherapy. Recently, we showed that the non-cytopathic lymphocytic choriomeningitis virus (LCMV) induces strong anti-tumor responses without directly killing tumor cells but by activation of CD8+ T cells. Here, we aim to generate an optimized arenavirus based on LCMV for application in cancer patients and its potential benefit with combination therapies. Methods We performed multiple passaging of the wild-type strain LCMV-WE in several murine and human cancer cells. The occurring mutations were identified and their role tested in vitro and in vivo in attenuated reassortant LCMV. Results We identified several mutations, which showed accelerated propagation in cancer cells leading to an attenuated reassortant arenavirus strain with accelerated entry in a broad spectrum of human cancer cells. This strain exhibited strong anti-tumoral efficacy in a variety of tumor models with minimal replication in healthy tissues and no severe disease symptoms in immune compromised murine model systems. Dissecting the anti-tumoral mechanism revealed that tumor-specific T cells were expanded, recruited to tumors and differentiated into potent effector cells. Furthermore, this virus strain amplified the anti-tumoral activity of a BiTE (Trp1/CD3) and combination with CAR- T cells to increase anti-tumor efficacy. In non-human primates, treatment with this strain led to increase in virus-mediated cytokine levels as well as T cells in the blood by maintaining a safe application. Conclusion In conclusion, by using the biological principle of mutation and selection, we developed an arenavirus-based immune therapy safely applied in preclinical model systems and GLP studies as well as harboring a unique mode of action and anti-tumoral efficacy. Combination with T cell-directed therapies including BITEs and CAR-T cells resulted in strong synergistic anti-tumoral responses. Funding Source Abalos Therapeutics; BMBF KMUi Topic Categories Translational and Interventional Immunology (TI)