title: Optimization of T-cell Reactivity by Exploiting TCR Chain Centricity for the Purpose of Safe and Effective Antitumor TCR Gene Therapy.
abstract: Adoptive transfer of T cells redirected by a high-affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains. In this study, we comprehensively studied how TCR chain centricity affects reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1(235-243) (A24/WT1(235)) and cross-reactive with B*57:01 (B57). The TAK1β, but not the TAK1α, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCRα counter-chains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1β-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1(235) and/or to B57. T cells reconstituted with these TCRα genes along with TAK1β possessed a very broad range (>3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically unselected TCRs.
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Munehide
authors.initials: M
authors.lastname: Nakatsugawa
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Kenji
authors.initials: K
authors.lastname: Chamoto
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Takara Bio, Inc., Otsu, Shiga, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tingxi
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology, Clinical Immunology and Infectious Disease, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.affiliation: Immune Therapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Department of Immunology, University of Toronto, Toronto, Ontario, Canada. naoto.hirano@utoronto.ca.
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D005818:Genetic Engineering / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D059871:HLA-A24 Antigen / Q000378:metabolism; D015235:HLA-B Antigens / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D009842:Oligopeptides / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014161:Transduction, Genetic; D025721:WT1 Proteins / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D059871:HLA-A24 Antigen; D015235:HLA-B Antigens; D020930:MAP Kinase Kinase Kinases; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D025721:WT1 Proteins; D000099151:MAP Kinase Kinase Kinase 7; C542271:CMTWNQMNL peptide; C438506:HLA-A*24:02 antigen; C484830:HLA-B*57:01 antigen