Optimizing T-cell receptor avidity with somatic hypermutation

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Adoptive T-cell therapy efficacy relies on high T-cell receptor (TCR) avidity.
• Endogenous TCRs targeting tumor-associated antigens (TAAs) often have low affinity due to central tolerance.
• Generating high-avidity anti-TAA TCRs is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To develop a novel in vitro system for directed evolution of TCR avidity.
• To enhance the avidity of the Pmel-1 TCR specific for the H-2D^b-gp100_25-33 melanoma antigen.
• To evaluate the therapeutic potential of engineered TCRs in preclinical cancer models.

Main Methods:

• Utilized somatic hypermutation (SHM) for directed evolution of TCR avidity.
• Introduced point mutations into the Pmel-1 TCR sequence.
• Transduced primary T cells with engineered TCRs and assessed their activity in vitro and in vivo.

Main Results:

• Identified 44 point mutations that enhance Pmel-1 TCR avidity.
• TCRs with two or three mutations showed enhanced in vitro activity.
• A triple-mutant TCR significantly improved in vivo therapy, reducing tumor size and improving survival in mice.

Conclusions:

• TCR avidity maturation via SHM is a viable strategy to enhance adoptive T-cell therapy.
• Engineered TCRs with optimized avidity demonstrate potent antitumor activity.
• This approach holds promise for improving cancer immunotherapy efficacy.