Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy is a significant advancement for blood cancers.
• Limited treatment persistence and cytokine release syndrome (CRS) hinder wider clinical use.

Purpose of the Study:

• To reframe the understanding of the CAR-T cell persistence versus CRS dilemma.
• To explore strategies for designing CAR-T cells with enhanced persistence and reduced toxicity.

Main Methods:

• Review of intracellular signaling networks within CAR-T cells.
• Analysis of the tumor microenvironment's influence on CAR-T cell function and inflammation.
• Exploration of novel CAR-T cell design strategies.

Main Results:

• Dynamic imbalance in signaling networks and TME inflammation contribute to poor CAR-T cell persistence and CRS.
• CAR-T cell persistence and inflammatory response are jointly regulated by intracellular networks and the TME.
• Strategies exist to simultaneously improve CAR-T cell persistence and mitigate CRS risk.

Conclusions:

• Persistence and safety of CAR-T cells are not mutually exclusive.
• Precise modulation can enhance CAR-T cell persistence and reduce CRS.
• This review provides a framework for developing safer and more persistent next-generation CAR-T cell therapies.