Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

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

doi:10.1038/s41467-021-25605-4

Title: Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Journal Article · 05 September 2021 · Nature Communications

DOI: https://doi.org/10.1038/s41467-021-25605-4 · OSTI ID:1875640

Hwang, Michael S. ^[1];

^[2]; Thirawatananond, Puchong ^[3];

^[4];

^[5]; Hsiue, Emily Han-Chung ^[4];

^[6]; Aytenfisu, Tihitina Y. ^[3]; Murphy, Michael B. ^[7];

^[3]; Skora, Andrew D. ^[8];

^[4];

^[4]; Bettegowda, Chetan ^[3]; Pardoll, Drew M. ^[9];

^[3]; Kinzler, Kenneth W. ^[10];

^[11] more »

Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Genentech, Inc., South San Francisco, CA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Walter and Eliza Hall Inst. of Medical Research, Parkville (Australia); Howard Hughes Medical Inst., Chevy Chase, MD (United States); Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Howard Hughes Medical Inst., Chevy Chase, MD (United States); Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States); Johns Hopkins Univ., Baltimore, MD (United States)
Cytiva, Marlborough, MA (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Eli Lilly and Co, San Diego, CA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States)
Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States); Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States)
Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States); Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD (United States)

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 IDH2^R140Q-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.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: National Cancer Institute; National Institutes of Health; National Institutes of Health Cancer Center Support; USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0012704

OSTI ID:: 1875640

Report Number(s):: BNL-223138-2022-JACI

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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An approved in vitro approach to preclinical safety and efficacy evaluation of engineered T cell receptor anti-CD3 bispecific (ImmTAC) molecules Harper, Jane; Adams, Katherine J.; Bossi, Giovanna PLOS ONE, Vol. 13, Issue 10 https://doi.org/10.1371/journal.pone.0205491	journal	October 2018
Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology Watanabe, Keisuke; Kuramitsu, Shunichiro; Posey, Avery D. Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.02486	journal	October 2018
Targeting the MHC Ligandome by Use of TCR-Like Antibodies Høydahl, Lene Støkken; Frick, Rahel; Sandlie, Inger Antibodies, Vol. 8, Issue 2 https://doi.org/10.3390/antib8020032	journal	May 2019
Getting the Most Out of Your Crystals: Data Collection at the New High-Flux, Microfocus MX Beamlines at NSLS-II Miller, Michelle; Maheshwari, Sweta; Shi, Wuxian Molecules, Vol. 24, Issue 3 https://doi.org/10.3390/molecules24030496	journal	January 2019
Class I HLA Folding and Antigen Presentation in β2-Microglobulin-Defective Daudi Cells Martayan, Aline; Sibilio, Leonardo; Tremante, Elisa The Journal of Immunology, Vol. 182, Issue 6 https://doi.org/10.4049/jimmunol.0802316	journal	March 2009
The Impact of a Large and Frequent Deletion in the Human TCR β Locus on Antiviral Immunity Brennan, Rebekah M.; Petersen, Jan; Neller, Michelle A. The Journal of Immunology, Vol. 188, Issue 6 https://doi.org/10.4049/jimmunol.1102675	journal	March 2012
Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains Harris, Daniel T.; Hager, Marlies V.; Smith, Sheena N. The Journal of Immunology, Vol. 200, Issue 3 https://doi.org/10.4049/jimmunol.1700236	journal	December 2017
CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia Xie, Guozhu; Ivica, Nikola A.; Jia, Bin figshare https://doi.org/10.6084/m9.figshare.12922520.v1	dataset	January 2020
Collaboration gets the most out of software Morin, Andrew; Eisenbraun, Ben; Key, Jason eLife, Vol. 2 https://doi.org/10.7554/eLife.01456	journal	September 2013

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