Engineering TME-gated inducible CAR-T cell therapy for solid tumors

Area of Science:

• Immunology
• Biotechnology
• Cancer Therapy

Background:

• Chimeric antigen receptor (CAR)-T cell therapy offers revolutionary cancer treatment.
• CAR-T cell therapy faces challenges with on-target, off-tumor toxicities due to imprecise activation.
• Advanced regulatory control systems are needed to enhance CAR-T cell precision and safety.

Purpose of the Study:

• To develop a novel CAR-T cell strategy with enhanced tumor selectivity and safety.
• To create a next-generation CAR-T cell, TME-iCAR-T, capable of sensing multiple tumor-specific characteristics.
• To integrate chemically induced proximity (CIP) and tumor-activated prodrugs for precise CAR-T cell regulation.

Main Methods:

• Designed a genetic "AND" gate system integrating abscisic acid (ABA)-based CIP and reactivity-based caging/sensing technology.
• Developed hypoxia-responsive small-molecule prodrugs by conjugating ABA with nitroaromatic derivatives.
• Utilized specific cancer signals within the tumor microenvironment (TME) to activate prodrugs and control CAR-T cell function.

Main Results:

• TME-iCAR-T cells demonstrated specific responses to combined tumor signals in vitro.
• Achieved cancer signal-restricted activation and enhanced cytotoxicity against cancer cells.
• Showcased controllability and significant antitumor efficacy in a xenograft prostate tumor model.

Conclusions:

• The developed TME-iCAR-T cell strategy offers a promising approach for precise cancer cell targeting.
• This modular multi-criteria control system enhances tumor selectivity and safety in cell-based immunotherapies.
• Represents a significant advancement in overcoming CAR-T cell-related toxicities for improved cancer treatment outcomes.