Rational Protein Engineering to Enhance MHC-Independent T-cell Receptors.

Area of Science:

• Immunology
• Synthetic Biology
• Protein Engineering

Background:

• Chimeric antigen receptor (CAR)-based therapies are synthetic cellular immunotherapies with limited long-term efficacy.
• Dysregulated CAR T-cell activation leads to T-cell dysfunction and therapeutic failure.

Purpose of the Study:

• To design and develop novel MHC-independent T-cell receptors (miTCRs) that overcome limitations of current CAR T-cell therapies.
• To improve the precision and durability of engineered T-cell responses for enhanced cancer immunotherapy.

Main Methods:

• Designed miTCRs by linking antibody variable domains to T-cell receptor constant chains.
• Utilized predictive modeling and iterative sequence modifications to optimize hybrid receptor structure.
• Evaluated miTCR T-cell function and persistence in multiple tumor models, including in vivo leukemic control with 41BB costimulation.

Main Results:

• Identified biochemical conflicts in standard synthetic receptor design and developed structure-enhanced miTCRs.
• Structure-enhanced miTCRs significantly improved receptor-driven T-cell function across various tumor models.
• 41BB costimulation prolonged miTCR T-cell persistence and enhanced leukemic control compared to CAR T cells.

Conclusions:

• Synthetic receptor structure is critical for regulating T-cell function and therapeutic efficacy.
• Structure-informed design of miTCRs provides a framework for engineering more durable and effective T-cell immunotherapies.
• Improved miTCRs offer a promising strategy to enhance the durability and efficacy of engineered T-cell therapies.