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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.

SUBMITTER: Bethune MT 

PROVIDER: S-EPMC6233129 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Bethune Michael T MT   Li Xiao-Hua XH   Yu Jiaji J   McLaughlin Jami J   Cheng Donghui D   Mathis Colleen C   Moreno Blanca Homet BH   Woods Katherine K   Knights Ashley J AJ   Garcia-Diaz Angel A   Wong Stephanie S   Hu-Lieskovan Siwen S   Puig-Saus Cristina C   Cebon Jonathan J   Ribas Antoni A   Yang Lili L   Witte Owen N ON   Baltimore David D  

Proceedings of the National Academy of Sciences of the United States of America 20181022 45


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  ...[more]

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