Precision Tumor Recognition by T Cells With Combinatorial Antigen-Sensing Circuits

Area of Science:

• Immunology
• Cancer Biology
• Synthetic Biology

Background:

• Chimeric antigen receptors (CARs) and T cell receptors (TCRs) redirect T cells to target cancer.
• Current T cell therapies face limitations due to the scarcity of tumor-specific antigens and on-target, off-tumor toxicities.
• Targeting multiple antigens simultaneously can improve therapeutic efficacy and specificity.

Purpose of the Study:

• To engineer a novel T cell circuit for enhanced tumor targeting and safety.
• To develop dual-receptor AND-gate T cells activated only by combinatorial antigens.
• To assess the in vivo efficacy and specificity of these engineered T cells.

Main Methods:

• Constructed a synthetic Notch receptor responsive to one tumor antigen.
• Engineered the synthetic Notch receptor to induce the expression of a chimeric antigen receptor (CAR) for a second antigen.
• Utilized dual-receptor AND-gate T cells for in vivo testing against tumors with single and combinatorial antigen expression.

Main Results:

• Engineered T cells demonstrated precise activation only in the presence of both target antigens.
• These dual-receptor T cells effectively eliminated tumors expressing combinatorial antigens.
• Importantly, single-antigen bystander tumors were spared, indicating high specificity and reduced off-tumor toxicity.

Conclusions:

• Combinatorial antigen recognition via dual-receptor AND-gate T cells offers a powerful strategy for cancer immunotherapy.
• This approach significantly enhances the safety and efficacy of T cell-based therapies.
• Precision dual-receptor circuits broaden the scope of targetable tumors and improve therapeutic outcomes.