Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Engineered T cell therapies, including CAR-T, are successful in blood cancers but limited in solid tumors.
• Current strategies often cause immune toxicities and undesirable T cell states.
• Need for enhanced T cell function and controlled immune responses in solid tumor treatment.

Purpose of the Study:

• To develop a novel modular receptor platform, Hybrid Receptors (Hybrid-Rs), for precise T cell control.
• To integrate chimeric antigen receptor (CAR) and SyNthetic Intramembrane Proteolysis Receptor (SNIPR) features.
• To enable antigen-dependent T cell activation coupled with programmable gene regulation.

Main Methods:

• Designed Hybrid Receptors (Hybrid-Rs) by integrating CAR and SNIPR functionalities.
• Demonstrated Hybrid-Rs enable antigen-dependent T cell activation and gene regulation.
• Showcased precise control over T cell potency, differentiation, and payload expression.
• Validated compatibility with human T cells and genome editing techniques.

Main Results:

• Hybrid-Rs provide context-dependent control over T cell potency and differentiation.
• Enabled conditional expression of immunotherapeutic payloads, mitigating toxicity.
• Demonstrated successful humanization and compatibility with precision genome editing in primary human T cells.
• Established a practical platform for clinical translation.

Conclusions:

• Hybrid Receptors offer a modular platform for advanced T cell therapies.
• This approach allows precise control of T cell function for solid tumor treatment.
• Hybrid-Rs present a promising strategy to overcome limitations of current T cell therapies and reduce toxicity.