EXTH-34. LOCAL DELIVERY OF AN IL-15 SUPERAGONIST USING A REPLICATING RETROVIRUS SYNGERIZES WITH TEMOZOLOMIDE TO INCREASE LYMPHOCYTE INFILTRATION AND SURVIVAL IN TWO POORLY IMMUNOGENIC GLIOBLASTOMA MOUSE MODELS

Abstract

Abstract Glioblastoma (GBM) leads to systemic and local immunosuppression and immunotherapies have had limited clinical success. We evaluated the treatment efficacy of RLI (receptor-linker-IL-15), a superagonist of T-cell activator IL-15, delivered to tumor cells using a tumor-selective retroviral replicating vector (RRV) in the syngeneic murine SB28 and Tu2449 GBM models, which are poorly immunogenic with low-mutational burden and known resistance to immunotherapy, similar to human GBM. RRV-RLI replicated and spread in cultured SB28 murine GBM cells with robust production of functional RLI (165.4 ± 5.3 ng/mL). Stereotactic injection of RRV-RLI into pre-established intracerebral Tu2449 tumors led to complete eradication of intracerebral tumors with long term survival (median not reached) in > 85% of treated mice vs. median survival of 12.5 days in control mice (p=0.001). Treated mice demonstrated significantly increased CD8 T cell infiltration. These mice also demonstrated immunologic memory to intracranial rechallenge. In SB28, RRV-RLI delivery into intracerebral tumors reduced tumor growth on bioluminescence imaging, and increased median survival compared to controls (55 vs. 19 days, p=0.002), with long-term survival in 12% of treated mice. Combining RRV-RLI treatment with systemically administered temozolomide (TMZ) in the SB28 model provided long term survival (median not reached) in >60% of treated mice. Immunologic analysis of treated tumors revealed a significant increase in CD8 T cell (2.1% to 20.5% of CD45 cells) and Natural Killer cell (1.4% to 9.6% of CD45 cells )infiltration in RLI-RRV+TMZ mice vs. PBS+TMZ mice. RLI was not detected in the blood of treated mice, and tumor-localized RRV-RLI gene delivery showed no adverse systemic immune effects. In summary, RRV-mediated RLI immunotherapy results in immunostimulatory changes that are further potentiated by systemically administered temozolomide. This tumor-localized gene therapy has the potential to synergize with standard of care treatment to reverse the immunosuppressed GBM tumor microenvironment and provide a significant treatment benefit.