Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Author:

Hwang Michael S.,Miller Michelle S.ORCID,Thirawatananond Puchong,Douglass JacquelineORCID,Wright Katharine M.ORCID,Hsiue Emily Han-Chung,Mog Brian J.ORCID,Aytenfisu Tihitina Y.,Murphy Michael B.,Aitana Azurmendi P.ORCID,Skora Andrew D.,Pearlman Alexander H.ORCID,Paul SumanORCID,DiNapoli Sarah R.ORCID,Konig Maximilian F.ORCID,Bettegowda Chetan,Pardoll Drew M.,Papadopoulos NickolasORCID,Kinzler Kenneth W.,Vogelstein BertORCID,Zhou ShibinORCID,Gabelli Sandra B.ORCID

Abstract

AbstractChimeric 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.

Funder

Lustgarten Foundation

Commonwealth Fund

Burroughs Wellcome Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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