In recent years, Chimeric Antigen Receptor T-cell (CAR-T) therapy has garnered significant attention for its remarkable efficacy, especially in treating patients with relapsed or refractory lymphoma. In this issue, we invited Dr. Hu Kai, Director of the Lymphoma and Myeloma Department at Beijing GoBroad Hospital, to explain the principles, therapeutic effects, and groundbreaking progress of CAR-T therapy in depth.

 

CAR-T Therapy: From “Reprogramming Immune Cells” to Precision Anti-Cancer Treatment

 

1. Engineering Immune Cells for Tumor Recognition and Killing

T cells play a central role in the immune system by monitoring and eliminating cancerous cells and combating external pathogens. However, in cancer patients, T cells often lose their ability to identify and kill tumor cells due to dysfunction.

CAR-T therapy involves extracting a patient’s T cells and genetically modifying them in a lab to express a Chimeric Antigen Receptor (CAR) on their surface. This receptor enables T cells to recognize specific antigens on tumor cells, thereby restoring their tumor-killing function. Once engineered, the T cells are reinfused into the patient’s body, where they actively seek out and destroy cancer cells.

 

2. Precision Therapy with Advantages over Conventional Treatments

Unlike traditional chemotherapy, which non-selectively kills both cancerous and healthy cells, CAR-T therapy targets tumor-specific antigens, thereby minimizing damage to normal cells and reducing side effects. It also overcomes drug resistance seen in chemotherapy and has shown efficacy in relapsed and refractory cases. Moreover, CAR-T cells exhibit persistence and immune memory, offering patients longer remission periods.

 

3. Manageable Adverse Effects with Growing Clinical Experience

CAR-T cells may cause Cytokine Release Syndrome (CRS) and neurotoxicity during tumor cell destruction, manifesting as fever, fatigue, or altered mental status. However, with accumulating clinical experience, these effects are now effectively managed with medications. As tumor burden decreases, acute toxicity symptoms generally subside.

Long-term toxicities like immunodeficiency may occur but can be mitigated with immunoglobulin infusions and timely interventions, greatly improving treatment safety.

 

CAR-T: A New Hope for Curing Relapsed/Refractory Lymphoma and Myeloma

 

CAR-T therapy has been well established for diseases such as B-cell lymphoma, B-cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma, with abundant clinical data supporting its safety and efficacy.

 

1. CD19 CAR-T for B-cell Lymphoma: A Classic Targeting Success

B-cell lymphoma was one of the first indications for approved CAR-T therapy. In relapsed/refractory cases, CAR-T has shown superior efficacy over traditional therapies and has become the recommended first-line salvage therapy in global guidelines.
CD19, a highly expressed B-cell surface marker, was one of the earliest CAR targets. CD19 CAR-T has delivered excellent outcomes in DLBCL, mantle cell lymphoma, and B-ALL. Data from our center shows an overall response rate of 70–80% in relapsed/refractory B-cell lymphoma, with 40–50% achieving progression-free survival of over five years—meeting the criteria for clinical cure.

 

2. CD19 CAR-T for B-ALL: Outstanding Short-term Efficacy

CD19 CAR-T therapy yields ~90% overall response rate and 60–70% complete remission in relapsed/refractory B-ALL. However, its long-term efficacy remains a challenge, especially for high-risk patients or those with residual disease post-treatment, where allogeneic hematopoietic stem cell transplantation may still be needed.

 

3. BCMA CAR-T Brings New Hope to Myeloma Patients

For heavily treated, refractory myeloma patients, BCMA CAR-T therapy shows ~80% response rate and ~60% complete remission. Although remission often lasts 1–2 years, CAR-T offers hope where conventional therapies have failed.

 

4. Emerging Targets, Multi-targeted & Enhanced CAR-T Products

To overcome tumor escape and improve outcomes, researchers are developing CAR-Ts targeting CD22, CD20, and dual-target formats (e.g., CD19/CD22), as well as enhanced CAR-Ts with cytokine-modulating properties. “Relay-style” multi-target strategies are explored to extend remission, such as switching from CD19 to CD22 CAR-T after relapse.

In multiple myeloma, GPRC5D has emerged as a promising target beyond BCMA, with early clinical data showing good efficacy and safety.

 

5. Universal CAR-T: A Breakthrough for Cell Source Limitations

Traditional CAR-T relies on patient-derived T cells, which may be dysfunctional after extensive chemotherapy. Universal CAR-T uses healthy donor cells, enabling “off-the-shelf” production for wider access. Despite some immunologic and expansion challenges, universal CAR-T continues to improve in feasibility and safety.

 

CD7 CAR-T: Breakthrough in T-cell Lymphoma

 

T-cell lymphoma is rare, heterogeneous, and difficult to treat. Our center has developed CAR-T therapies targeting CD7 and CD5 for these challenging diseases.

1. Challenges in T-cell CAR-T Therapy

• Cell sourcing: Many patients lack viable T cells for CAR-T manufacturing.
• Fratricide: T-cell CAR-Ts may attack each other during expansion. This issue is being technically addressed.
• Prolonged immune suppression: T-cell depletion post-therapy may require stem cell transplantation to restore immunity.

2. Clinical Strategies for T-cell CAR-T

• Early treatment before excessive chemotherapy damage is critical.
• Plan for hematopoietic stem cell transplant post-CAR-T, especially in aggressive subtypes.
• Treat during low tumor burden to enhance response and reduce toxicity.
• Use allogeneic or universal CAR-T when autologous cells are unavailable.

Despite challenges, with proper patient selection and timing, T-cell CAR-T offers a hopeful option with superior outcomes over repeated chemotherapy.

 

Toward Personalized & Comprehensive Care for Maximal Benefit

The rapid evolution of CAR-T therapy is transforming the landscape of hematologic malignancies—from B to T cells, from single to multi-targets, from autologous to universal formats.

In addition, therapies like bispecific antibodies and antibody-drug conjugates (ADCs) are enriching the treatment toolbox across disease stages.

Ultimately, tailoring treatment plans to the patient’s disease biology, tolerance, and prognosis is key to maximizing therapeutic efficacy and improving survival outcomes.