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Tumor Immunotherapy

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Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.

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

Kole T Roybal¹, Levi J Rupp¹, Leonardo Morsut¹

¹Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.

|February 3, 2016

Summary

Engineered T cells with dual-receptor AND-gate circuits precisely target tumors expressing two antigens. This approach enhances safety by sparing healthy tissues and expanding cancer immunotherapy options.

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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.