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Updated: Oct 21, 2025
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Michael S Hwang1,2,3,4, Michelle S Miller2,5,6,7, Puchong Thirawatananond5
1Ludwig Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract:
Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2R140Q-HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.
Insights
Researchers developed a novel chimeric antigen receptor (CAR) T-cell therapy targeting a specific mutation in isocitrate dehydrogenase 2 (IDH2) found in cancers. This advancement addresses the challenge of limited tumor-specific antigens for effective CAR T-cell therapy.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating cancers but is limited by a lack of tumor-specific antigens.
- Identifying and targeting cancer-specific mutations is crucial for advancing CAR T-cell therapy.
Purpose of the Study:
- To develop a CAR T-cell therapy targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) mutation (R140Q).
- To engineer CARs for enhanced sensitivity and specificity against the IDH2R140Q-HLA-B*07:02 neoantigen.
Main Methods:
- Development of a CAR targeting the IDH2R140Q mutation presented with HLA-B*07:02.
- Engineering of the CAR hinge domain and optimization of the targeting moiety guided by crystal structure analysis.
Main Results:
- Successful development of a CAR targeting the specific IDH2R140Q-HLA-B*07:02 complex.
- Enhanced sensitivity and specificity of the engineered CARs for the targeted neoantigen.
Conclusions:
- This novel CAR T-cell approach effectively targets an HLA-restricted neoantigen arising from a common cancer mutation.
- The strategy holds potential for developing immunotherapies against other challenging cancer driver mutations.
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