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Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice
Padma Kadiyala1,2, Stephen V Carney1,2, Jessica C Gauss1,2
1Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
The Journal of Clinical Investigation
|December 17, 2020
Summary
Inhibiting D-2HG in mutant IDH1 (mIDH1) gliomas boosts survival and immunity. Combining D-2HG inhibition with radiation, temozolomide, and anti-PDL1 therapy leads to complete tumor regression in mice.
Area of Science:
- Oncology
- Cancer Metabolism
- Immunology
Background:
- Mutant isocitrate dehydrogenase 1 (mIDH1) is a key marker in adult gliomas.
- Lower-grade mIDH1 gliomas are molecularly classified by 1p/19q codeletion/TERT-promoter mutations or ATRX/TP53 inactivation.
- This study investigates mIDH1, ATRX, and TP53-inactivated glioma subtypes.
Purpose of the Study:
- To explore the role of D-2-hydroxyglutarate (D-2HG) in the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas.
- To evaluate the efficacy of D-2HG inhibition, alone and in combination with standard therapies, in preclinical models.
- To assess the impact of D-2HG inhibition on anti-glioma immunity and T cell responses.
Main Methods:
- D-2HG inhibition was tested as monotherapy and combined with radiation and temozolomide (IR/TMZ) in mIDH1 glioma mouse models.
- PD-L1 expression levels were analyzed in response to D-2HG inhibition.
- Combination therapy including D-2HG inhibition, IR/TMZ, and anti-PDL1 immune checkpoint blockade was evaluated for tumor regression and immunological memory.
Main Results:
- D-2HG inhibition, alone or with IR/TMZ, increased median survival in mIDH1 glioma-bearing mice.
- D-2HG inhibition induced anti-mIDH1 glioma immunological memory and increased PD-L1 expression.
- The combination of D-2HG inhibition, IR/TMZ, and anti-PDL1 resulted in complete tumor regression in 60% of mice, reduced T cell exhaustion, and promoted memory CD8+ T cell generation.
Conclusions:
- Metabolic reprogramming via D-2HG inhibition can elicit anti-glioma immunity, enhancing survival and immunological memory.
- Combination therapy targeting D-2HG metabolism, radiation, chemotherapy, and immune checkpoints shows significant preclinical efficacy.
- These findings support the clinical investigation of IDH-R132H inhibitors combined with IR/TMZ and anti-PDL1 for treating mIDH1/mATRX/mTP53 gliomas.
