Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Michael S. Hwang, Michelle S. Miller, Puchong Thirawatananond, Jacqueline Douglass, Katharine M. Wright, Emily Han-Chung Hsiue, Brian J. Mog, Tihitina Y. Aytenfisu, Michael B. Murphy, P. Aitana Azurmendi, Andrew D. Skora, Alexander H. Pearlman, Suman Paul, Sarah R. DiNapoli, Maximilian F. Konig, Chetan Bettegowda, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein (), Shibin Zhou () and Sandra B. Gabelli ()
Additional contact information
Michael S. Hwang: Johns Hopkins University School of Medicine
Michelle S. Miller: Howard Hughes Medical Institute
Puchong Thirawatananond: Johns Hopkins University School of Medicine
Jacqueline Douglass: Johns Hopkins University School of Medicine
Katharine M. Wright: Howard Hughes Medical Institute
Emily Han-Chung Hsiue: Johns Hopkins University School of Medicine
Brian J. Mog: Johns Hopkins University School of Medicine
Tihitina Y. Aytenfisu: Johns Hopkins University School of Medicine
Michael B. Murphy: Cytiva
P. Aitana Azurmendi: Johns Hopkins University School of Medicine
Andrew D. Skora: Johns Hopkins University School of Medicine
Alexander H. Pearlman: Johns Hopkins University School of Medicine
Suman Paul: Johns Hopkins University School of Medicine
Sarah R. DiNapoli: Johns Hopkins University School of Medicine
Maximilian F. Konig: Johns Hopkins University School of Medicine
Chetan Bettegowda: Johns Hopkins University School of Medicine
Drew M. Pardoll: Sidney Kimmel Comprehensive Cancer Center
Nickolas Papadopoulos: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Johns Hopkins University School of Medicine
Bert Vogelstein: Johns Hopkins University School of Medicine
Shibin Zhou: Johns Hopkins University School of Medicine
Sandra B. Gabelli: Johns Hopkins University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25605-4

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DOI: 10.1038/s41467-021-25605-4

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