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

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

  • Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):E10702-E10711. doi: 10.1073/pnas.1810653115.
Michael T Bethune 1,  Xiao-Hua Li 2,  Jiaji Yu 2 3,  Jami McLaughlin 2,  Donghui Cheng 2,  Colleen Mathis 2,  Blanca Homet Moreno 4,  Katherine Woods 5 6 7,  Ashley J Knights 7,  Angel Garcia-Diaz 4,  Stephanie Wong 1,  Siwen Hu-Lieskovan 4,  Cristina Puig-Saus 4,  Jonathan Cebon 5 6 7,  Antoni Ribas 4 8 9 10 11,  Lili Yang 12 8 9 10,  Owen N Witte 12 8 11,  David Baltimore 13
Affiliations

Affiliations

  • 1 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
  • 2 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095.
  • 3 Molecular Biology Institute, University of California, Los Angeles, CA 90095.
  • 4 Division of Hematology and Oncology, Department of Medicine, University of California, Los Angeles, CA 90095.
  • 5 Cancer Immunobiology Laboratory, Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, VIC 3084, Australia.
  • 6 School of Cancer Medicine, La Trobe University, Bundoora, VIC 3086, Australia.
  • 7 Cancer Immunobiology Laboratory, Ludwig Institute for Cancer Research, Heidelberg, VIC 3084, Australia.
  • 8 Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095.
  • 9 Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095.
  • 10 Department of Medicine, University of California, Los Angeles, CA 90095.
  • 11 Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, CA 90095.
  • 12 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; liliyang@ucla.edu owenwitte@mednet.ucla.edu baltimo@caltech.edu.
  • 13 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; liliyang@ucla.edu owenwitte@mednet.ucla.edu baltimo@caltech.edu.
PMID: 30348802 DOI: 10.1073/pnas.1810653115
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.

Keywords

MHC; NY-ESO-1; T cell receptor gene therapy; TCR; immunotherapy.

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