IMMU-31. DAMAGE RESPONSE FROM SYSTEMIC RNA VACCINATION RESTORES HUMORAL IMMUNITY IN GLIOBLASTOMA

Abstract Therapies against glioblastoma (GBM) remain stymied by poor penetration across the blood-brain barrier (BBB) and systemic immunotolerance. These outcomes necessitate development of therapies simultaneously targeted to tumors while engineering peripheral immunity to co-localize for synergistic responses. We developed RNA loaded lipid particles (LPs) to simultaneously function as inducers of cytotoxic responses in the GBM tumor microenvironment (TME) and as systemic activators of peripheral immunity. RNA-LP mediated response was studied in mice bearing KR158b tumors and in canines and humans with spontaneous glioma and glioblastoma respectively. We found that RNA-LPs could localize to the brain TME of animals bearing murine gliomas and rapidly upregulate damage associated signaling pathways including p53-CDKN2A. This correlates with increased gene signatures for complement and proteosome processing. Simultaneously, in the periphery, RNA-LPs increase integrin expression on activated T cells and ICAM expression in brain tumors helping steer T cell translocation across the BBB. In canines with malignant gliomas, response to RNA-LPs correlated with increasing tumor size suggesting pseudoprogression. Similar to murine glioma, canine gliomas harvested within 48h of vaccine administration demonstrated rapid increases in complement and p53 pathway activation. In one human patient treated with RNA-LPs per NCT04573140 (PNOC020 trial), we demonstrate biopsy confirmed pseudoprogression with increases in p53 pathway signaling and complement activation. In post-treatment tumor biopsy samples, there was increased hyperexpanded post-infusion intratumoral IgH clones. Systemic administration of RNA-LP elicits damage response in the TME that predisposes complement activation and humoral immunity. Coupled with peripheral recruitment of T cells that can translocate across the BBB, RNA-LPs elicit potent bi-directional adaptive immunotherapy against GBM.