• Ravi Medikonda, John Choi, Ayush Pant, Laura Saleh, Denis Routkevitch, Luqing Tong, Zineb Belcaid, KimYoung HoonYH2Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Christopher M Jackson, Christina Jackson, Dimitrios Mathios, Yuanxuan Xia, Pavan P Shah, Kisha Patel, Timothy Kim, Siddhartha Srivastava, Sakibul Huq, Jeff Ehresman, Zach Pennington, Betty Tyler, Henry Brem, and Michael Lim.
• 1Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
• J. Neurosurg. 2022 Feb 1; 136 (2): 379388379-388.

ObjectiveImmune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM.MethodsC57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry.ResultsThe BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05).ConclusionsIn this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

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