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Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma
Ravi Medikonda1, John Choi1, Ayush Pant1
11Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
Objective:
Immune 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.
Methods:
C57BL/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.
Results:
The 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).
Conclusions:
In 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.
Insights
Combining anti-programmed cell death protein 1 (anti-PD-1) immunotherapy with glutamate modulation using BHV-4157 shows synergistic effects in glioblastoma (GBM) models. This combination therapy enhances survival by modulating the tumor microenvironment and relies on CD4+ and CD8+ T cells.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Cancer Metabolism
Background:
- Anti-programmed cell death protein 1 (anti-PD-1) immunotherapy shows limited efficacy in glioblastoma (GBM).
- Glioblastoma exhibits immunosuppression, necessitating combination strategies.
- Elevated glutamate in the GBM tumor microenvironment (TME) may contribute to immunosuppression.
Purpose of the Study:
- To investigate the potential synergy between glutamate modulation and anti-PD-1 immunotherapy in GBM.
- To evaluate the efficacy of a novel glutamate modulator, BHV-4157, in combination with anti-PD-1 therapy.
- To elucidate the role of glutamate in GBM immunosuppression and the mechanism of combination therapy.
Main Methods:
- Utilized a syngeneic GL261 glioblastoma mouse model.
- Administered anti-PD-1 immunotherapy, BHV-4157, or combination therapy.
- Assessed overall survival, tumor microenvironment glutamate levels via microdialysis, and immune cell populations (CD4+, CD8+, Foxp3+) via immunofluorescence and flow cytometry.
Main Results:
- Combination therapy significantly improved median overall survival compared to control.
- BHV-4157 treatment led to a significant decrease in TME glutamate levels.
- BHV-4157 treatment increased intratumoral CD4+ T cells and decreased Foxp3+ T cells.
- Survival benefit of BHV-4157 was dependent on the presence of CD4+ and CD8+ T cells.
Conclusions:
- Glutamate modulation in combination with anti-PD-1 immunotherapy demonstrates synergistic efficacy in GBM.
- The synergistic effect is mediated through T cell-dependent mechanisms, involving CD4+ and CD8+ T cells.
- Targeting glutamate in the GBM TME represents a promising strategy for enhancing immunotherapy outcomes.
