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 VogelsteinShibin Zhou, Sandra B. Gabelli

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number5271
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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