HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer Journal Article


Authors: Foley, K. C.; Spear, T. T.; Murray, D. C.; Nagato, K.; Garrett-Mayer, E; Nishimura, M. I.
Article Title: HCV T Cell Receptor Chain Modifications to Enhance Expression, Pairing, and Antigen Recognition in T Cells for Adoptive Transfer
Abstract: T cell receptor (TCR)-gene-modified T cells for adoptive cell transfer can mediate objective clinical responses in melanoma and other malignancies. When introducing a second TCR, mispairing between the endogenous and introduced alpha and beta TCR chains limits expression of the introduced TCR, which can result in impaired efficacy or off-target reactivity and autoimmunity. One approach to promote proper TCR chain pairing involves modifications of the introduced TCR genes: introducing a disulfide bridge, substituting murine for human constant regions, codon optimization, TCR chain leucine zipper fusions, and a single-chain TCR. We have introduced these modifications into our hepatitis C virus (HCV) reactive TCR and utilize a marker gene, CD34t, which allows us to directly compare transduction efficiency with TCR expression and T cell function. Our results reveal that of the TCRs tested, T cells expressing the murine Cbeta2 TCR or leucine zipper TCR have the highest levels of expression and the highest percentage of lytic and interferon-gamma (IFN-gamma)-producing T cells. Our studies give us a better understanding of how TCR modifications impact TCR expression and T cell function that may allow for optimization of TCR-modified T cells for adoptive cell transfer to treat patients with malignancies.
Journal Title: Molecular therapy oncolytics
Volume: 5
ISSN: 2372-7705; 2372-7705
Publisher: Unknown  
Journal Place: United States
Date Published: 2017
Start Page: 105
End Page: 115
Language: eng
DOI/URL:
Notes: LR: 20170624; GR: P01 CA154778/CA/NCI NIH HHS/United States; GR: R01 CA104947/CA/NCI NIH HHS/United States; JID: 101666776; OTO: NOTNLM; 2017/04/20 [received]; 2017/05/13 [accepted]; epublish