Editor’s Note: Chimeric Antigen Receptor T-cell Therapy (CAR-T) is a novel cellular immunotherapy technology that has shown excellent efficacy in the treatment of refractory relapsed diffuse large B-cell lymphoma (DLBCL). Despite this, a significant number of patients do not respond to the treatment or experience relapse and progression. How to further improve the efficacy of CAR-T cells is a key focus of future research. At the recently held “2024 Nanjing Lymphoma Forum,” Professor Wenbin Qian from The Second Affiliated Hospital of Zhejiang University School of Medicine delivered a brilliant report titled “Mechanisms of CAR-T Resistance Based on DLBCL Pathological Characteristics and Countermeasures.” After the conference, “Oncology Frontier – Hematologie Frontier” invited Professor Wenbin Qian for an interview to further discuss this topic.
Oncology Frontier – Hematologie Frontier: CAR-T therapy, as an emerging immunotherapy, shows great potential in the treatment of diffuse large B-cell lymphoma (DLBCL). Could you briefly introduce the current status of CAR-T treatment for DLBCL and the challenges it faces?
Professor Wenbin Qian: Currently, two CD19 CAR-T cell therapies have been approved in China for the treatment of DLBCL. In clinical practice, the Hematology Department of the Second Affiliated Hospital of Zhejiang University School of Medicine has treated nearly 40 patients with CAR-T therapy, achieving good results. In terms of efficacy, the clinical application results in Chinese patients are similar to international clinical trial data, and in terms of side effects, especially immune effector cell-associated neurotoxicity syndrome (ICANS), we observed lower toxicity.
The main limitations of CAR-T therapy in clinical application are high cost and low accessibility. As a “living” cell drug, the CAR-T therapy process is complex and subject to strict regulation. Currently, CAR-T is priced at 1.2 million and 1.29 million yuan, with overall treatment costs being high. Although some regions have commercial insurance that covers part of the costs, accessibility remains low. Additionally, the autologous CAR-T preparation process is complex, requiring the collection of peripheral blood mononuclear cells from the patient, which usually takes two to three weeks. Some patients progress too quickly and unfortunately cannot receive CAR-T treatment. Therefore, we hope that in the future, CAR-T cell therapy can become more affordable. Moreover, universal CAR-T therapy is also a future development direction, offering better accessibility and clinical application convenience.
Oncology Frontier – Hematologie Frontier: The mechanisms of CAR-T resistance are complex, involving multiple aspects such as antigen escape and immunosuppressive microenvironment. Could you explain in detail the possible mechanisms of CAR-T resistance based on the pathological characteristics of DLBCL?
Professor Wenbin Qian: Research indicates that the occurrence rate of resistance due to antigen escape is about 20% to 30%, suggesting that most resistance is due to other comprehensive factors, including the tumor immune microenvironment and T cell exhaustion caused by PD-1/PD-L1 immune checkpoints. Another important reason for CAR-T resistance is the tumor cells’ resistance to apoptosis. Clinically, many factors and patient pathophysiological characteristics, such as large tumor masses, poor performance status, and P53 mutations, are associated with poorer CAR-T efficacy.
Many research teams are currently working to further modify CAR-T cells. For example, fourth-generation CAR-T cells, also known as armored CAR-T cells, can overcome tumor immune microenvironment factors or reduce T cell exhaustion. Our team has also developed fourth-generation CAR-T cells for the treatment of refractory relapsed large B-cell lymphoma, achieving a median progression-free survival (PFS) of 13 months, significantly higher than the historical median PFS of 6 months. This suggests that novel CAR-T cells may overcome some resistance and improve the efficacy of CAR-T cell therapy for large B-cell lymphoma.
Oncology Frontier – Hematologie Frontier: In clinical practice, there are currently no effective strategies to address CAR-T resistance. What are your insights and research findings on countermeasures for CAR-T resistance in DLBCL treatment?
Professor Wenbin Qian: Activation of immune checkpoint signaling pathways can lead to T cell exhaustion. Our team has developed CAR-T cell therapies targeting the PD-1/PD-L1 signaling pathway, achieving good results. Additionally, combination therapies, such as combining PD-1 antibodies or demethylation treatments, can improve CAR-T efficacy. We conducted a small sample study on CAR-T combined with PD-1 antibody treatment, achieving a median PFS of 23 months, though this finding needs further confirmation through larger sample, prospective clinical studies.
Furthermore, some targeted drugs, such as BTK inhibitors (ibrutinib, zanubrutinib, orelabrutinib) combined with CAR-T therapy, can improve efficacy. Other methods, such as autologous hematopoietic stem cell transplantation, can also improve CAR-T efficacy by enhancing the tumor microenvironment. For example, the Hematology Department team at Wuhan Tongji Hospital has achieved good results with autologous hematopoietic stem cell transplantation combined with CAR-T cell immunotherapy in CNS-involved lymphoma and P53-mutated DLBCL.
Oncology Frontier – Hematologie Frontier: Looking to the future, what challenges and opportunities do you see in the study of CAR-T resistance? What are your expectations and suggestions for improving CAR-T efficacy?
Professor Wenbin Qian: DLBCL is highly heterogeneous, and the mechanisms of CAR-T resistance are complex. Clinically, we lack large-scale, randomized controlled trials to confirm which interventions can improve CAR-T efficacy. In the future, we need large-scale clinical studies and even randomized controlled trials to validate the effectiveness of these interventions, providing better evidence-based medicine for clinical treatment.
There are various interventions, especially with the emergence of new immunotherapies such as bispecific antibodies, which may play an important role in CAR-T combination therapy in the future. Our team has achieved encouraging results with CAR-NK cell therapy for DLBCL, showing promise as a universal cell therapy. Additionally, many biotech companies in China are actively developing CAR-T therapies. With continuous technological advancement and in-depth research and development, we expect more affordable and accessible products to be available, meeting the unmet needs of clinicians and patients.
Expert Profile:
Professor Wenbin Qian
– Chief Physician
– Doctoral Supervisor
– Director of the Hematology Department, Second Affiliated Hospital of Zhejiang University School of Medicine
– Member of the Hematology Physician Branch of the Chinese Medical Doctor Association
– Standing Member of the Oncology Hematology Committee of the Chinese Anti-Cancer Association
– Standing Member of the Hematologic Oncology Committee of the Chinese Anti-Cancer Association
– Member of the Lymphoma Committee of the Chinese Anti-Cancer Association
– Deputy Chairman of the Lymphoma Committee of the Chinese Elderly Health Care Association
– Member of the Lymphocyte Disease Group and Infection Group of the Chinese Society of Hematology
– Chairman of the Hematology Branch of the Zhejiang Medical Association
– Vice President of the Hematology Physician Branch of the Zhejiang Medical Doctor Association
– Deputy Chairman of the Hematology and Lymphoma Committee of the Zhejiang Anti-Cancer Association
– Published over 90 SCI papers in international journals such as Clin Cancer Res, Leukemia, J Hematol & Oncol, Signal Transduction and Target Therapy, Cell Mol Immunol, Blood Cancer Journal, Cancer Communication, and Lancet Hematology as the first/corresponding author
– Principal investigator or major member in key projects funded by the National Natural Science Foundation of China, National Key Research and Development Program of China, and provincial key research and development plans, with two National Science and Technology Progress Second Prizes and nearly ten provincial Science and Technology Progress First and Second Prizes
