Inhibition of D-2HG leads to upregulation of a proinflammatory gene signature in a novel HLA-A2/HLA-DR1 transgenic mouse model of IDH1R132H-expressing glioma.

Abstract

BACKGROUND:

Long-term prognosis of WHO grade II, isocitrate dehydrogenase (IDH)-mutated low-grade glioma (LGG) is poor due to high risks of recurrence and malignant transformation into high-grade glioma. Immunotherapy strategies are attractive given the relatively intact immune system of patients with LGG and the slow tumor growth rate. However, accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) in IDH-mutated gliomas leads to suppression of inflammatory pathways in the tumor microenvironment, thereby contributing to the 'cold' tumor phenotype. Inhibiting D-2HG production presents an opportunity to generate a robust antitumor response following tumor antigen vaccination and immune checkpoint blockade.

METHODS:

An IDH1R132H glioma model was created in syngeneic HLA-A2/HLA-DR1-transgenic mice, allowing us to evaluate the vaccination with the human leukocyte antigens (HLA)-DR1-restricted, IDH1R132H mutation-derived neoepitope. The effects of an orally available inhibitor of mutant IDH1 and IDH2, AG-881, were evaluated as monotherapy and in combination with the IDH1R132H peptide vaccination or anti-PD-1 immune checkpoint blockade.

RESULTS:

The HLA-A2/HLA-DR1-syngeneic IDH1R132H cell line expressed the IDH1 mutant protein and formed D-2HG producing orthotopic gliomas in vivo. Treatment of tumor-bearing mice with AG-881 resulted in a reduction of D-2HG levels in IDH1R132H glioma cells (10 fold) and tumor-associated myeloid cells, which demonstrated high levels of intracellular D-2HG in the IDH1R132H gliomas. AG-881 monotherapy suppressed the progression of IDH1R132H gliomas in a CD4+ and CD8+ cell-dependent manner, enhanced proinflammatory IFNγ-related gene expression, and increased the number of CD4+ tumor-infiltrating T-cells. Prophylactic vaccination with the HLA-DR1-restricted IDH1R132H peptide or tumor-associated HLA-A2-restricted peptides did not enhance survival of tumor-bearing animals; however, vaccination with both HLA-A2-IDH1R132H and DR1-IDH1R132H peptides in combination with the IDH inhibitor significantly prolonged survival. Finally, tumor-bearing mice treated with both AG-881 and a PD-1 blocking antibody demonstrated improved survival when compared with either treatment alone.

CONCLUSION:

The development of effective IDH1R132H-targeting vaccine may be enhanced by integration with HLA class I-restricted cytotoxic T cell epitopes and AG-881. Our HLA-A2/HLA-DR1-syngeneic IDH1R132H glioma model should allow us to evaluate key translational questions related to the development of novel strategies for patients with IDH-mutant glioma.

• Authors: Pavlina Chuntova, Akane Yamamichi, Tiffany Chen, Rohini Narayanaswamy, Sebastien Ronseaux, Christine Hudson, Adriana E Tron, Marc L Hyer, Megan Montoya, Abigail L Mende, Takahide Nejo, Kira M Downey, David Diebold, Min Lu, Brandon Nicolay, Hideho Okada
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 5 (05 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35606087 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Cancer Vaccines
• Glutarates
• HLA-A2 Antigen
• HLA-DR1 Antigen
• Immune Checkpoint Inhibitors
• Vaccines, Subunit
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase

Topics

• Animals
• Cancer Vaccines
• Glioma (drug therapy, genetics, pathology)
• Glutarates
• HLA-A2 Antigen (genetics)
• HLA-DR1 Antigen (genetics)
• Humans
• Immune Checkpoint Inhibitors
• Isocitrate Dehydrogenase (genetics)
• Mice
• Mice, Transgenic
• Tumor Microenvironment
• Up-Regulation
• Vaccines, Subunit