A Vaccine Targeting Mutant IDH1 Induces Antitumor Immunity (S22.001)

OBJECTIVE: To explore whether the frequent IDH1R132H mutation in glioma patients can be exploited for a mutation-specific vaccine BACKGROUND: Mutations in the gene for isocitrate dehydrogenase type 1 (IDH1) in gliomas almost uniformly occur in critical arginine residues in the catalytic pocket (132), resulting in cellular transformation and tumor growth. From an immunological perspective, the regional uniformity of IDH mutations predisposes the mutated epitope as a potential tumor-specific neoantigen suitable for targeted immunotherapy. DESIGN/METHODS: Peptide libraries encompassing the mutated region of IDH1 were generated. Blood from patients with IDH1R132H-mutated and IDH1 wildtype gliomas was analyzed for IDH1R132H-specific antibodies and T cells using ELISA, ELISpot assays and flow cytometry. Mice transgenic for human major histocompatibility complex MHC classes I (A2) and II (DR1) were used for peptide vaccination studies to analyze mutation-specific T- and B-cell responses. A syngeneic model of IDH1R132H mutant tumors was established in these humanized mice. In vivo depletion studies addressed the relevance of distinct immune subsets. IDH1R132H-specific tetramers were generated to characterize tumor-infiltrating mutation-specific T cells. RESULTS: Peptides encompassing the mutated IDH1R132H were presented on human class II major histocompatibility complexes to stimulate proinflammatory mutation-specific CD4+ T helper 1 responses. Patients with IDH1R132H-mutated gliomas harbor IDH1R132H-specific CD4+ T helper 1 cells and IgG1 antibodies. Vaccination of humanized A2.DR1 transgenic mice bearing syngeneic IDH1R132H-mutated tumors resulted in a mutation-specific antitumor immune response and control of established tumors, which were infiltrated by IDH1R132H-specific T cells. Tumors that escaped the mutation-specific vaccine had lost IDH1R132H expression. The therapeutic efficacy was dependent on CD4+ T cells and B cells. CONCLUSIONS: As IDH1R132H is an early mutation present in all tumor cells of most low grade and anaplastic gliomas, a mutation-specific anti-IDH1-vaccine represents a viable novel therapeutic strategy for IDH1R132H-mutated gliomas. The design of a phase I/II clinical trial is presented. Study Supported by: Disclosure: Dr. Platten has nothing to disclose. Dr. Schumacher has nothing to disclose. Dr. Bunse has nothing to disclose. Dr. Sahm has nothing to disclose. Dr. Pusch has nothing to disclose. Dr. Quandt has nothing to disclose. Dr. Menn has nothing to disclose. Dr. Osswald has nothing to disclose. Dr. Riemer has nothing to disclose. Dr. Beckhove has nothing to disclose. Dr. Friese has nothing to disclose. Dr. von Deimling has nothing to disclose. Dr. Wick has received personal compensation for activities with Roche Diagnostics Corp., Merck Sharp & Dohme Ltd. Dr. Wick has received personal compensation in an editorial capacity for CNS Oncology. Dr. Wick has received research support from Boehringer Ingelheim Pharmaceuticals Inc., Apogenix, and Merck Sharp & Dohme Ltd.