Understanding CAR-T
Explore the science behind chimeric antigen receptor (CAR) T-cell therapy and its technological evolution.
The Evolution of CAR Architecture
From First- to Fourth-Generation CARs: Continuous Innovation Driving More Precise and Durable Cell Therapy
- The evolution of CAR-T technology has progressed from basic antigen recognition to enhanced T-cell activation, followed by functional optimization and advanced engineering strategies. To address key challenges such as antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment, CAR architectures continue to evolve with the goal of achieving more durable, precise, and controllable antitumor activity.
- Today, second-generation CARs remain the foundation of commercially approved CAR-T therapies. Building on this success, third-generation, fourth-generation, and other next-generation engineered CAR designs are being actively developed to further expand the therapeutic potential of cell therapy.
First-Generation CAR The Foundation of CAR-T Therapy
- Featured only the primary activation domain (e.g., CD3ζ), demonstrating that genetically engineered T cells could recognize and eliminate tumor cells through an artificial receptor.
- However, due to the absence of co-stimulatory signaling, first-generation CARs showed limited in vivo expansion and persistence, and were primarily used to establish the proof of concept for CAR-T technology.
Second-Generation CAR The Predominant Architecture for Commercial CAR-T Therapies
- Building upon the first-generation design, second-generation CARs incorporate a single co-stimulatory domain, significantly enhancing T-cell activation, expansion, and persistence. The most commonly used co-stimulatory domains are CD28 and 4-1BB. Today, second-generation CARs remain the predominant architecture in commercially approved CAR-T therapies worldwide.
- 4-1BB is one of the most widely adopted co-stimulatory domains in second-generation CARs. Studies have shown that 4-1BB signaling supports CAR-T cell expansion, long-term persistence, and the maintenance of memory T-cell phenotypes, providing a structural foundation for durable antitumor activity.¹˒²
- In recent years, several newly approved commercial CAR-T therapies have adopted 4-1BB-based CAR designs, underscoring its important role in the continued optimization of CAR architecture.
Third-Generation CAR Exploring Enhanced Co-stimulatory Activation
- Building upon the second-generation CAR design, third-generation CARs incorporate two co-stimulatory domains to further enhance T-cell activation, function, and persistence.
- While third-generation CARs represent an important step in the continued evolution of CAR engineering, second-generation CARs remain the predominant architecture in commercially approved CAR-T therapies. Third-generation CARs continue to be investigated and optimized in both preclinical and clinical studies.
Fourth-Generation CAR From Tumor Cell Killing to Tumor Microenvironment Modulation
- Fourth-generation CARs are generally based on the second-generation CAR architecture, with the addition of functional modules such as cytokine secretion, immune-modulatory mechanisms, or built-in safety switches.
- Beyond directly targeting tumor cells, these next-generation designs aim to modulate the tumor microenvironment, enhance immune coordination, and improve the precision and controllability of CAR-T therapy.
Multi-Mechanism Synergistic Design Exploring the Long-Term Therapeutic Potential of Next-Generation CAR-T
Systematically Designed to Address Mechanisms of Relapse
JWCAR239 incorporates a dual-target, dual-CAR architecture targeting both CD19 and CD20, together with multiple functional enhancement modules designed to address key challenges in CAR-T therapy, including antigen escape, limited CAR-T persistence, and the immunosuppressive tumor microenvironment.
Multiple Mechanisms to Enhance Long-Term Therapeutic Potential
By modulating Fas/FasL-mediated apoptotic signaling, supplementing CD58-associated co-stimulatory signaling, and blocking TGF-β-mediated immunosuppression, JWCAR239 is designed to enhance CAR-T cell persistence, functional activity, and resilience within the immunosuppressive tumor microenvironment, thereby supporting long-term antitumor efficacy.
Rapid Manufacturing Designed to Preserve Favorable T-cell Phenotypes
JWCAR239 utilizes a rapid manufacturing process intended to shorten ex vivo culture time, helping preserve early memory T-cell characteristics while maintaining robust cell expansion capacity and in vitro antitumor activity.
Advancing into Clinical Evaluation
JWCAR239 is currently being evaluated in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). Preliminary observations indicate that the product has demonstrated a favorable safety and tolerability profile, with antitumor activity, in vivo CAR-T cell expansion, and persistence observed even at lower dose levels.