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. 2019 Nov 15;145(10):2816-2826.
doi: 10.1002/ijc.32612. Epub 2019 Aug 24.

Optimizing T-cell receptor avidity with somatic hypermutation

David Bassan  1 , Yosi Meir Gozlan  1 , Adi Sharbi-Yunger  1 , Esther Tzehoval  1 , Lea Eisenbach  1
Affiliations

Optimizing T-cell receptor avidity with somatic hypermutation

David Bassan et al. Int J Cancer. .

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-2Db -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.

Keywords: TCR; adoptive cell transfer; avidity maturation; cancer immunotherapy; somatic hypermutation.

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References

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