CaltechAUTHORS
  A Caltech Library Service

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

Bethune, Michael T. and Li, Xiao-Hua and Yu, Jiaji and McLaughlin, Jami and Cheng, Donghui and Mathis, Colleen and Homet Moreno, Blanca and Woods, Katherine and Knights, Ashley J. and Garcia-Diaz, Angel and Wong, Stephanie and Hu-Lieskovan, Siwen and Puig-Saus, Cristina and Cebon, Jonathan and Ribas, Antoni and Yang, Lili and Witte, Owen N. and Baltimore, David (2018) Isolation and characterization of NY-ESO-1–specific T cell receptors restricted on various MHC molecules. Proceedings of the National Academy of Sciences of the United States of America, 115 (45). E10702-E10711. ISSN 0027-8424. PMCID PMC6233129. https://resolver.caltech.edu/CaltechAUTHORS:20181023-133725439

[img] PDF - Published Version
Creative Commons Attribution Non-commercial No Derivatives.

2441Kb
[img] PDF (Appendix) - Supplemental Material
Creative Commons Attribution Non-commercial No Derivatives.

638Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20181023-133725439

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1810653115DOIArticle
http://www.pnas.org/content/suppl/2018/10/19/1810653115.DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233129PubMed CentralArticle
ORCID:
AuthorORCID
Witte, Owen N.0000-0003-4461-4533
Baltimore, David0000-0001-8723-8190
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.
Funders:
Funding AgencyGrant Number
NIH5P01CA132681-5
Prostate Cancer Foundation15CHAL02
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
NIHR35 CA197633
Ressler Family FundUNSPECIFIED
Parker Institute for Cancer ImmunotherapyUNSPECIFIED
National Health and Medical Research Council (NHMRC)1007381
National Health and Medical Research Council (NHMRC)487905
Victorian State GovernmentUNSPECIFIED
NIH5P30 A1028697
Subject Keywords:NY-ESO-1; immunotherapy; T cell receptor gene therapy; TCR; MHC
Issue or Number:45
PubMed Central ID:PMC6233129
Record Number:CaltechAUTHORS:20181023-133725439
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20181023-133725439
Official Citation:Isolation and characterization of NY-ESO-1–specific T cell receptors restricted on various MHC molecules. Michael T. Bethune, Xiao-Hua Li, Jiaji Yu, Jami McLaughlin, Donghui Cheng, Colleen Mathis, Blanca Homet Moreno, Katherine Woods, Ashley J. Knights, Angel Garcia-Diaz, Stephanie Wong, Siwen Hu-Lieskovan, Cristina Puig-Saus, Jonathan Cebon, Antoni Ribas, Lili Yang, Owen N. Witte, David Baltimore. Proceedings of the National Academy of Sciences Nov 2018, 115 (45) E10702-E10711; DOI: 10.1073/pnas.1810653115
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90372
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Oct 2018 21:34
Last Modified:15 Apr 2020 23:12

Repository Staff Only: item control page