Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Current T-cell therapies target single tumor antigens, risking damage to healthy tissues due to antigen overlap.
• Limited identification of truly tumor-specific antigens hinders the development of effective T-cell therapies.

Purpose of the Study:

• To develop a T-cell engineering strategy for tumor targeting in the absence of a single tumor-restricted antigen.
• To enhance the specificity and safety of T-cell therapies by requiring dual-antigen recognition.

Main Methods:

• T cells were engineered to express both a chimeric antigen receptor (CAR) for suboptimal activation and a chimeric costimulatory receptor (CCR) for a second antigen.
• The dual-receptor system was tested using prostate tumor antigens PSMA and PSCA.

Main Results:

• Co-transduced T cells effectively destroyed tumors expressing both PSMA and PSCA.
• T cells did not damage tumors expressing only PSMA or only PSCA, demonstrating antigen-specific targeting.
• This dual-targeting approach significantly improved tumor specificity.

Conclusions:

• The 'tumor-sensing' strategy enables T-cell therapies to target tumors based on dual-antigen expression, overcoming the limitations of single-antigen targeting.
• This approach holds promise for broadening the application of T-cell therapies and mitigating off-tumor side effects.