Overcoming the blood-brain barrier with nanoparticle vaccines against gliomas

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Project Summary While activated T cells cross the blood-brain barrier (BBB), immunotherapy has yet to be harnessed for targeted therapy due to GBM’s heterogeneity and immunosuppressive microenvironment. Unleashing immunotherapy against GBM requires new technologies that activate the tumor microenvironment (TME), while concomitantly engaging both innate and adaptive arms to generate sustained cellular immunity. We developed a novel RNA-nanoparticle (RNA-NP) formulation to simultaneously orchestrate innate/adaptive response against a heterogeneous cohort of personalized tumor derived mRNA. By layering tumor mRNA into a multi-lamellar nano-lipid formulation (for systemic administration), we can deliver increased antigenic load (per particle) triggering potent innate activation which then facilitates adaptive effector responses. Our technology unlocks activity in poorly immunogenic small animal and spontaneous large animal glioma models. RNA-NPs activate systemic/intratumoral dendritic cells (DCs), upregulate critical innate gene signatures in the glioma TME, and induce glioma-specific T cell immunity. In murine tumor models resistant to immune checkpoint inhibitors, RNA-NPs induce robust anti-tumor efficacy with long-term survivor benefits. We have previously demonstrated safety of RNA-NPs in acute/chronic murine GLP toxicity studies, and launched a large animal canine glioma trial (IACUC#201609430). Our canine trial demonstrated that RNA-NP administration is feasible, safe and immunologically active with improvement in overall survival in pet dogs with terminal gliomas (compared with historical controls). We have since received FDA-IND approval (BB-IND#19304, Sayour) for first-in-human studies in GBM patients. In this proposal, we will explore mechanistic underpinnings for innate modulation and adaptive response following RNA-NPs. Our experiments will be conducted in clinically relevant small and large animal glioma models, which recapitulate many human GBM features before translation into a human clinical trial. We hypothesize that RNA-NPs reprogram the glioma microenvironment unlocking vaccine response across the BBB. Our SPECIFIC AIMS will be to: 1. Establish RNA-NPs as innate biomodulators of glioma immunogenicity. 2. Elucidate mechanistic interactions between innate and adaptive anti-glioma immunity following tumor specific RNA-NPs. 3. Determine in a neoadjuvant clinical trial design the modulating effects and immunogenicity of RNA- NPs in recurrent GBM patients.