1. Optimizing T-cell receptor avidity with somatic hypermutation.
- Author
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Bassan D, Gozlan YM, Sharbi-Yunger A, Tzehoval E, and Eisenbach L
- Subjects
- Animals, Cell Line, Tumor, HEK293 Cells, Histocompatibility Antigen H-2D, Humans, Immunotherapy, Adoptive methods, Melanoma, Experimental immunology, Mice, Mice, Transgenic, Mutagenesis, Site-Directed methods, Peptides immunology, Point Mutation, Proof of Concept Study, Receptors, Antigen, T-Cell immunology, Skin Neoplasms immunology, Directed Molecular Evolution methods, Melanoma, Experimental therapy, Receptors, Antigen, T-Cell genetics, Skin Neoplasms therapy, gp100 Melanoma Antigen immunology
- Abstract
Adoptive transfer of T cells that have been genetically modified to express an antitumor T-cell receptor (TCR) is a potent immunotherapy, but only if TCR avidity is sufficiently high. Endogenous TCRs specific to shared (self) tumor-associated antigens (TAAs) have low affinity due to central tolerance. Therefore, for effective therapy, anti-TAA TCRs with higher and optimal avidity must be generated. Here, we describe a new in vitro system for directed evolution of TCR avidity using somatic hypermutation (SHM), a mechanism used in nature by B cells for antibody optimization. We identified 44 point mutations to the Pmel-1 TCR, specific for the H-2D
b -gp10025-33 melanoma antigen. Primary T cells transduced with TCRs containing two or three of these mutations had enhanced activity in vitro. Furthermore, the triple-mutant TCR improved in vivo therapy of tumor-bearing mice, which exhibited improved survival, smaller tumors and delayed or no relapse. TCR avidity maturation by SHM may be an effective strategy to improve cancer immunotherapy., (© 2019 UICC.)- Published
- 2019
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