Mutant IDH1 Is an Effective Immunotherapeutic Target for Glioma

Point mutations in isocitrate dehydrogenase type 1 (IDH1) occur early in glioma development and cause an increase in genomic hypermethylation, genetic instability, and malignant transformation. Due to its uniform expression, mutant IDH1 represents a potential antigenic target through mutation-specific vaccination, prompting Schumacher, Bunse, and colleagues to assess the antigenicity of IDH1 mutated at arginine 132 (R132H). Screening of peptide libraries containing the R132H mutation using predictive MHC algorithms and binding assays demonstrated specific binding to MHC class II but not to common MHC class I alleles, suggesting the presence of a CD4⁺ T-cell epitope. Consistent with this idea, vaccination of mice expressing human MHC genes with mutant IDH1 peptide induced an IFNγ CD4⁺ T-helper 1 (T_H1)–cell response and production of antibodies targeting mutant IDH1. Importantly, the wild-type peptide did not induce T-cell activity, indicating that these immune responses were mutation-specific. Furthermore, analysis of glioma patient samples revealed spontaneous mutant-IDH1–specific CD4⁺ T-cell responses and the presence of anti-IDH1 R132H antibodies in a subset of patients with IDH1 R132H–mutated gliomas, but not in patients with wild-type IDH1 tumors, providing further evidence for the immunogenicity of mutant IDH1. Whole tumor-cell vaccination of human MHC-expressing mice with sarcomas harboring IDH1 R132H mutations induced a robust peptide-specific T-cell response, indicating that the mutant peptide was endogenously processed and presented on MHC class II molecules. Both prophylactic and therapeutic mutant-peptide vaccination resulted in growth suppression of transplanted IDH1 R132H–expressing but not wild-type IDH1–expressing sarcomas and were well tolerated. Of note, immunization generated an antigen-specific CD4⁺ but not CD8⁺ T-cell response that when depleted abrogated the effects of peptide vaccination, demonstrating that this antitumor efficacy is CD4⁺ T-cell dependent. Together, these findings demonstrate the potential for IDH1 mutation–specific vaccination strategies for the treatment of glioma and other tumors bearing this mutation.

Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 2014 Jun 25 [Epub ahead of print].