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Tumor Immunotherapy

Tumor Immunotherapy

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

Huong T X Nguyen¹, Byung-Gyu Kim², Jay T Myers³

¹Department of Chemistry, Case Western Reserve University (CWRU), Cleveland, OH, USA; Case Comprehensive Cancer Center, CWRU School of Medicine, Cleveland, OH, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy

|May 1, 2025

Summary

This summary is machine-generated.

Next-generation CAR-T cells, TME-iCAR-T, use a genetic AND gate to sense multiple tumor signals. This enhances cancer cell targeting and reduces toxicities for safer immunotherapies.

Keywords:

CAR-T cells CIP cancer signals small molecule solid tumors tumor microenvironment

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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.