IMMU-61. INHIBITION OF MUTANT IDH1 WITH AGI-5198 ENHANCES THE EFFICACY OF RADIOTHERAPY ELICITING IMMUNOLOGICAL MEMORY AND IMPROVING OVERALL SURVIVAL. (5th November 2018)

• Record Type: Journal Article
• Authors: Kadiyala, Padma; Nunez, Felipe; Li, Dan; Schwendeman, Anna; Lowenstein, Pedro; Castro, Maria
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi135
• Page End: vi135
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.564
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Mutant IDH1 gliomas have are heterogeneous tumors with a high incidence of relapse. We are studying a glioma subtype, genetically characterized by inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, TP53 and gain of function mutations in isocitrate dehyrdogenase 1 (mIDH1). Mutation in IDH1 converts α-ketoglutrate (αKG) to 2-hydroxyglutarate (2HG), an oncometabolite that inhibits histone and DNA demethylases, leading to a hypermethylated tumor phenotype. This leads to epigenetic reprograming of the tumor trancriptome. AGI-5198 a specific mIDH1inhibitor blocks the production of 2HG within the mIDH1 glioma cells. Our in-vitro data using AGI-5198 in combination with radiation, which is the standard of care for mIDH1 glioma patients, demonstrated that mIDH1 inhibition confers radiosensitivity to the tumor cells. To determine whether AGI-5198 would be an effective radiosensitizer in-vivo, we used a mIDH1 glioma transplantable mouse model. Animals were implanted with mIDH1 tumor cells and at day seven post tumor implantation; they were treated with radiation followed by administration of AGI-5198. With systemic delivery of AGI-5198, we observed 40% long term survivors(>90 days) in the single modality treatment. Our results also demonstrate that the combination of AGI-5198 and radiation therapy significantly prolongs the median survival (MS) of mIDH1 glioma bearing mice (~1.5 fold vs controls); eliciting strong antitumor activity, eradicating 40% of the established mIDH1 gliomas. In addition, when the long term survivors were rechallenged with mIDH1 tumor cells in the contralateral hemisphere, without further treatment, all the mice remained tumor free, indicating the development of anti-glioma immunological memory. Collectively, these findings support the clinical testing of AGI-5198 as an adjuvant therapy for patients with mIDH1 glioma.