Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma

SIMPLE SUMMARY: IDH-mutant low-grade gliomas (LGG) are slow-growing glial cell-derived tumors of the central nervous system (CNS) that predominantly manifest in young adults and often show malignant transformation. Despite the therapeutic advances in several other oncologic areas, they are still considered incurable. Immunotherapies offer new therapeutic opportunities; however, they remain ineffective in treating LGG patients. In this review, we aim to summarize the relevant preclinical and clinical research findings and discuss the challenges and lessons learned from those trials. Furthermore, future perspectives on improving the efficacy of immunotherapy for IDH-mutant LGG are highlighted. ABSTRACT: Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically “cold” tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG.