CTIM-11. MRNA AGGREGATES ELICIT RAPID IMMUNOLOGIC RESPONSE AND PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS

Abstract

Abstract BACKGROUND Glioblastoma immunotherapy trials remain limited by heterogeneity and the immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed a novel cancer immunotherapy that leverages use of mRNA lamellar aggregates (RNA-LPA) encoding for personalized glioblastoma antigens to simultaneously reprogram the GBM TME while inducing tumor specific immunity in the periphery. METHODS In a Phase I trial (PNOC020) with an embedded acceleration titration design (ATD) for patients with newly-diagnosed MGMT unmethylated glioblastoma, we sought to assess whether intravenous administration of RNA-LPAs encoding for pp65 mRNA (tumor associated antigen) mixed with personalized tumor mRNA (extracted and amplified from patient specific biopsies) could activate peripheral immunity while simultaneously reprogramming the GBM TME. All patients received surgical resection with adjuvant chemoradiation followed by escalating doses of RNA-LPA (0.625-1.5 µg/kg). RESULTS We have treated 3 patients on the ATD and one patient on the expanded Phase I trial. In all patients treated to date, RNA-LPAs elicited a rapid response (within hours) characterized by release of cytokines (IL-12, TNF-α, IFN-α), chemokines (CCL2, CCL4, CXCL9-10), increase in plasmacytoid dendritic cells and recruitment of peripheral blood mononuclear cells. Over time there was expansion of antigen specific T cells; T cell receptor (TCR) sequencing pre- and post-infusion demonstrated changes to the most prevalent clonotypes by ~10-20%. In the first subject treated on the expanded phase I trial, we observed significant immunologic response after the fourth vaccine, including 20-fold increase in IFN-γ inducible protein-10. One month after vaccine administration, there was marked increase in the enhancing areas on MRI, which on biopsy demonstrated no viable tumor cells and only reactive gliosis, necrosis, and lymphocytic infiltrates. CONCLUSION RNA-LPAs elicit rapid immune activation in the periphery and reprogram the GBM TME into a proinflammatory milieu as evidenced by tissue confirmed pseudoprogression.