Editors' ChoiceCancer

Using Mutant IDH1 to Arm the Immune System in Cancer

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Science Translational Medicine  16 Jul 2014:
Vol. 6, Issue 245, pp. 245ec123
DOI: 10.1126/scitranslmed.3009808

The immune system is tightly regulated; however, it is often suppressed in cancer. Recent efforts have focused on altering the immune system to target tumors by modulation of immune checkpoints or the development of antitumor vaccines. The success of immunotherapy approaches relies on the identification of tumor-specific alterations, which drive the development of targeted therapies. The recent discovery of a mutation in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in a variety of cancers such as gliomas and leukemias has revealed a new tumor-specific antigen and a promising candidate for immunotherapy. Schumacher and colleagues now used tissue from IDH1 glioma patients to develop a vaccine targeting mutant IDH1 and show that this vaccine induces an immune response and reduces tumor growth in mouse tumor models.

IDH1 is mutated in more than 70% of lower-grade gliomas (grade II and grade III) and represents an epitope suitable for vaccine development. The most common IDH1 mutation occurs at arginine 132 (R132H). The authors screened peptide libraries around the mutated region (R132H) to identify peptides that induced an interferon-γ (IFN-γ) response in T cells. The clinical relevance of this T cell response was confirmed in peripheral blood from glioma patients. The authors observed that a fraction of IDH1-mutant patients mounted an IFN-γ T cell response against mutant IDH1, but no response was detected in IDH1–wild-type patients. The authors also used wild-type and mutant IDH1 sarcoma models to demonstrate that peptide vaccination reduced the growth of mutant but not wild-type IDH1 tumors in mice. This effect was mediated by CD4+ T cells, depletion of which blocked the reduction in IDH1 tumor growth after IDH1 peptide vaccination.

These results demonstrate that mutant IDH1 can be targeted by a peptide vaccine strategy. Future studies evaluating this approach in glioma models and human patients will help facilitate the translation of this therapeutic strategy to the clinical setting.

T. Schumacher et al., A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 10.1038/nature13387 (2014). [Abstract]

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