Principal Investigator Heinrich Heine University Hospital, United States
Disclosure(s):
Philipp A. Lang, Prof: No relevant disclosure to display
Introduction/Rationale: 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.
