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.
Highlights
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
NetMHCpan, which predicts peptide binding to human leukocyte antigen (HLA) alleles, estimates that the mutant IDH2R140Q peptide will bind 200-fold tighter to the HLA-B*07:02 allomorph compared with other common HLA alleles
Positive selection was conducted with HLA-B*07:02 pHLA monomers containing the IDH2R140Q peptide, and negative selection was performed against pHLA monomers containing the IDH2WT peptide
Summary
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. 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. Mutated protein products derived from cancer driver genes, or mutation-associated neoantigens (MANAs), can be processed and presented as peptides by human leukocyte antigen (HLA) molecules[30,31,32]. Such altered peptides can form peptide-HLA (pHLA) complexes resulting in tumor-specific antigens that can be engaged at the cell surface[33,34,35,36,37,38]. T-cell receptormimic (TCRm) antibodies have been generated that can discern subtle differences between pHLA complexes derived from the protein products of cancer driver hotspot mutations (i.e., MANAs) and those from their wild-type (WT) counterparts[39,40]
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