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Published November 6, 2018 | Supplemental Material + Published
Journal Article Open

Isolation and characterization of NY-ESO-1–specific T cell receptors restricted on various MHC molecules

Abstract

Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. Due to the prevalence of the HLA-A2 MHC class I supertype in most human populations, the majority of TCR gene therapy trials targeting public antigens have employed HLA-A2–restricted TCRs, limiting this approach to those patients expressing this allele. For these patients, TCR gene therapy trials have resulted in both tantalizing successes and lethal adverse events, underscoring the need for careful selection of antigenic targets. Broad and safe application of public antigen-targeted TCR gene therapies will require (i) selecting public antigens that are highly tumor-specific and (ii) targeting multiple epitopes derived from these antigens by obtaining an assortment of TCRs restricted by multiple common MHC alleles. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we pilot an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2.

Additional Information

© 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Contributed by Owen N. Witte, September 26, 2018 (sent for review June 21, 2018; reviewed by Rafi Ahmed and Stephen P. Schoenberger). PNAS published ahead of print October 22, 2018. We thank John Lee for help setting up the IncuCyte, Nathanael Joshua Bangayan for help optimizing its operation, Christie Qin and Hoang Vu (Leo) Li for technical assistance with ELISA assays, Drake Smith for guidance with animal experiments, and the staff of the UCLA animal facility for animal husbandry. The MSGV vector was provided by Eugene Barsov and Richard Morgan. This work was supported by NIH Grant 5P01CA132681-5 (to D.B., O.N.W., A.R., and L.Y.) and Prostate Cancer Foundation Challenge Award 15CHAL02 (to D.B., O.N.W., L.Y., and M.T.B.). M.T.B. is the recipient of a Jane Coffin Childs Postdoctoral Fellowship. A.R. was supported by NIH Grant R35 CA197633, the Ressler Family Fund, and the Parker Institute for Cancer Immunotherapy. K.W. was supported by Australian National Health and Medical Research Council (NHMRC) Project Grant 1007381. J.C. was supported by an Australian NHMRC Practitioner Fellowship 487905 and by Operational Infrastructure Support Program funding from the Victorian State Government. Primary human PBMCs were purchased from the CFAR Virology Core Laboratory at the UCLA AIDS Institute (NIH Grant 5P30 A1028697). Author contributions: M.T.B., X.-H.L., J.Y., J.M., D.C., C.M., B.H.M., K.W., J.C., A.R., L.Y., O.N.W., and D.B. designed research; M.T.B., X.-H.L., J.Y., J.M., D.C., C.M., B.H.M., K.W., A.J.K., A.G.-D., S.W., S.H.-L., and C.P.-S. performed research; M.T.B., X.-H.L., J.Y., J.M., D.C., C.M., B.H.M., K.W., J.C., A.R., L.Y., O.N.W., and D.B. analyzed data; and M.T.B., X.-H.L., J.Y., L.Y., O.N.W., and D.B. wrote the paper. Reviewers: R.A., Emory University; and S.P.S., La Jolla Institute for Allergy and Immunology. Conflict of interest statement: A patent application has been filed (serial no. 62/727,485) entitled "Composition of NY-ESO-1-Specific T Cell Receptors Restricted on Multiple Major Histocompatibility Complex Molecules." This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1810653115/-/DCSupplemental.

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Supplemental Material - pnas.1810653115.sapp.pdf

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August 22, 2023
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