Versatile strategy for controlling the specificity and activity of engineered T cells

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Chimeric antigen receptor (CAR)-T-cell therapy shows promise for cancer treatment but faces limitations due to severe toxicities.
• Current CAR-T-cell therapies require improved safety mechanisms to broaden their clinical application.

Purpose of the Study:

• To develop novel "switch" molecules for precise control over CAR-T-cell activation and function.
• To enhance the safety and efficacy of CAR-T-cell therapy by modulating T-cell-cancer cell interactions.

Main Methods:

• Designed and synthesized semisynthetic "switch" molecules incorporating antibody fragments targeting CD19 and CD22, site-specifically modified with FITC.
• Utilized genetically encoded noncanonical amino acids for precise molecular modification.
• Developed a universal anti-FITC CAR-T-cell for controlled engagement with switch-modified cancer cells.

Main Results:

• Achieved precise control over the formation of complexes between target cancer cells and CAR-T cells.
• Demonstrated potent, dose-dependent in vivo antitumor activity in xenograft models.
• Observed reduced in vivo toxicity and elimination of B-cell aplasia in immune-competent mice, indicating improved safety.

Conclusions:

• The "switch" molecule system offers a method to titrate CAR-T-cell activity in vivo, enhancing safety and efficacy.
• This approach may enable the expansion of engineered T-cell therapy to solid tumors and other non-cancerous indications.