Development of a B Cell Based Vaccine for the Treatment of Newly Diagnosed Malignant Gliomas

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PROJECT 3: SUMMARY Immunotherapy has significantly improved the clinical outcome of many cancer patients. However, most glioblastoma (GBM) patients have not, so far, benefited from immunotherapeutic intervention. To explore alternative ways to potentiate the anti-GBM immunity, we've developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism, BAFF, and IFNg stimulation. In our preclinical study, BVax migrates to critical secondary lymphoid organs and is proficient at antigen cross-presentation, promoting the survival and functionality of tumor- infiltrating CD8+ T cells. In addition, BVax produces immunoglobulins (humoral immune response) reactive to the tumor. These immunoglobulins elicited a potent therapeutic effect. A combination of radiation, BVax, CD8 T cells and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This research proposal aims to translate BVax to the clinic to treat newly diagnosed malignant gliomas. To effectively implement this therapy in the clinic, we propose to perform IND-enabling studies to manufacture autologous BVax and CD8 T cells (Aim 1). Upon FDA approval, we aim to conduct a first-in-human BVax trial (Aim 2) and evaluate the effect on the immune response (Aim 3). We hypothesize that the proposed autologous cellular therapy is safe and effective at eliciting protective anti-GBM immunity via cellular and humoral immune responses. Overall, our study provides a novel alternative to current immunotherapeutic approaches.