A bacterial immunotherapeutic drives long-term immunity in Glioblastoma 2301770

Abstract

Abstract Introduction Glioblastoma (GBM) is the most aggressive primary brain tumor, with most patients succumbing to disease within 2 years. Current standard of care is ineffective with recurrence within 6 months, partly due to weak anti-tumor immune responses. Despite successes in other cancers, immunotherapies have largely failed in GBM because of its inherently immune-excluded and immunosuppressive nature. We report a genetically attenuated Brucella melitensis strain (BmΔvjbR) that targets tumors and modulates their immune microenvironment. Prior studies in non-brain tumors showed that BmΔvjbR promotes polarization of myeloid cells to an activated state and increases the number and function of CD8+ T cells. Here, we tested the hypothesis that BmΔvjbR can induce durable anti-tumor immunity in GBM. Methods BmΔvjbR therapeutic efficacy was tested in a syngeneic orthotopic CT2A high grade glioma mouse model, transduced with luciferase. Mice received an intratumoral injection of either PBS or 1.10^8 CFU BmΔvjbR. Mice were followed for survival, and tumor growth was monitored using bioluminescence imaging. Survivors were rechallenged with the same cell line and compared to age-matched naïve controls. Results BmΔvjbR treatment reduced tumor development and achieved 50% long-term survival, compared to PBS controls. Upon rechallenge, previously cured mice cleared established tumors resulting in 100% survival (n = 3), whereas age-matched controls (n = 8) developed tumors and the majority died. Conclusion These preliminary findings indicate that BmΔvjbR can elicit durable and protective anti-tumor immunity in GBM, reducing tumor progression and improving survival upon rechallenge. Ongoing exploration holds promise for uncovering the full therapeutic potential of bacterial-based strategies for reprogramming the immunosuppressive environment in GBM and other cancers. Funding Source Siteman cancer center pilot grant Topic Categories Vaccines and Immunotherapy (VAC)