From September 6 to 8, 2024, the 5th Tianjin International Lymphoma Conference was successfully held. The conference featured 12 specialized sessions, including immunotherapy, translational research, and new drug development, creating a platform for international academic exchange and cooperation. During the event, Hematology Frontier invited Dr. Wei Sang from The Affiliated Hospital of Xuzhou Medical University to provide an in-depth analysis of CAR-T cell therapy in different hematologic malignancies and explore strategies for optimizing treatment outcomes.

Hematology Frontier: CAR-T cell therapy has shown significant efficacy in treating hematologic malignancies. Based on your clinical experience, could you share the differences in CAR-T efficacy across various types of blood cancers? Additionally, could you explain the reasons behind these differences?

Dr. Wei Sang: In the current application of CAR-T therapy in lymphoma and hematologic malignancies, there are notable differences in efficacy. Based on existing clinical experience and research data, the early treatment results for acute B-lymphoblastic leukemia (B-ALL) are the most impressive, with response rates exceeding 90% for complete remission (CR). CAR-T therapy for lymphomas and myeloma shows similar short-term response rates, but long-term survival varies. These differences in CAR-T efficacy may be attributed to several factors:

First, the “tumor antigen load” is likely a key factor behind the efficacy differences in various blood cancers. Leukemia (a liquid tumor) patients often carry a high tumor antigen load, which allows CAR-T cells to be more easily activated. In contrast, lymphomas and myelomas have biological characteristics more akin to solid tumors, which significantly reduces the ability of CAR-T cells to be activated. In the future, treatment strategies may need to adjust the CAR-T cell infusion dose based on the patient’s antigen load. For example, in relapsed/refractory B-ALL, a dose of 105/kg may be effective and safer, whereas for relapsed/refractory classical Hodgkin lymphoma, a dose of 107/kg might be required to achieve the expected efficacy.

Second, the efficacy of CAR-T therapy is influenced by the patient’s immune status. Currently, most CAR-T products used in both commercial and clinical trial settings are autologous, which heavily relies on the functionality of the patient’s residual immune cells. Therefore, establishing a CAR-T treatment system based on immune status assessment and selecting patients better suited for CAR-T therapy may optimize treatment strategies. This would also have significant implications for guiding individualized CAR-T combination therapy plans.

Additionally, the timing of treatment is crucial for CAR-T efficacy. Most CAR-T products currently available are positioned as third-line therapies, but treatment strategies are gradually shifting toward second- and even first-line options. This trend is evident in several clinical studies, such as the success of axicabtagene ciloleucel (Axi-cel) in treating relapsed/refractory non-Hodgkin lymphoma in the ZUMA-1 trial, the exploration of second-line treatment in the ZUMA-7 trial, and the application of first-line treatment in the ZUMA-12 trial. This shift in treatment timing is associated with improved efficacy, not only in terms of increased CR and overall response rates (ORR), but also because early CAR-T intervention can prevent the immune damage caused by multiple lines of treatment, thereby preserving the patient’s immune cell function to better meet treatment challenges.

Lastly, the high heterogeneity of hematologic malignancies also plays a significant role in CAR-T efficacy. Lymphomas encompass over 100 different types, with significant variations in antigen expression, genetic molecular backgrounds, and microenvironments. Future research should focus on understanding these differences and exploring targeted CAR-T treatment strategies, which will be a key area of study for clinicians.

Hematology Frontier: How do you assess the long-term efficacy and relapse rates of CAR-T therapy? Are there any new strategies to further improve efficacy and reduce relapse risk?

Dr. Wei Sang: Despite the remarkable success of CAR-T therapy in treating hematologic malignancies, it still faces new challenges and bottlenecks. Recent data indicate that CAR-T cell efficacy has room for further improvement. According to the long-term follow-up results of the ZUMA-1 trial, the five-year overall survival (OS) rate was 42.6%, suggesting that there is still nearly 60% of potential improvement to explore.

Based on current clinical practice and experimental data, we have observed significant differences in the response of different blood cancers to CAR-T therapy. For example, multiple myeloma patients often achieve relatively long progression-free survival (PFS) after CAR-T treatment, whereas acute B-ALL patients tend to have poorer prognosis, with about 90% experiencing relapse within two years. The two-year relapse rate for large B-cell lymphoma patients is approximately 50%.

Therefore, the primary goals for CAR-T therapy should focus on two aspects: improving short-term response rates and extending long-term survival.

To achieve these goals, three strategies are worth exploring and attempting:

First, combination therapy may enhance the efficacy of CAR-T treatment. By combining existing immunotherapies, targeted therapies, and hematopoietic stem cell transplantation, we hope to improve both short-term efficacy and long-term survival outcomes.

Second, continuous improvement and optimization of CAR-T technology are crucial. Currently, most commercial CAR-T products are based on second-generation technology. In the future, upgrading to more advanced third- and fourth-generation technologies may lead to breakthroughs in efficacy.

Lastly, given the current reliance on the functionality of patients’ residual immune cells, we strongly recommend collecting and cryopreserving lymphocytes early, while the patient’s condition is favorable. This measure ensures that when CAR-T treatment is needed in the future, there will be a sufficient supply of healthy immune cells, thereby ensuring the success of the treatment and avoiding failure due to immune cell exhaustion. Clinical experience shows that 20% to 30% of patients who wish to receive CAR-T therapy in the late stages of their disease are unable to proceed due to immune cell exhaustion, highlighting the importance of early immune cell collection and cryopreservation.

Hematology Frontier: Cytokine release syndrome (CRS) and neurotoxicity are common adverse reactions associated with CAR-T therapy. Based on your clinical experience, are there any unique challenges in managing these adverse reactions in Chinese patients? What successful strategies have you implemented?

Dr. Wei Sang: Adverse events during CAR-T treatment, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often become obstacles or limitations to the clinical application of this therapy. According to current clinical experience and data, acute lymphoblastic leukemia (ALL) patients have a higher incidence of adverse events after CAR-T treatment, with early onset and significant safety risks. In comparison, lymphoma and myeloma patients, such as those with diffuse large B-cell lymphoma (DLBCL), generally experience fewer adverse reactions, likely due to differences in disease state and tumor burden.

Specifically, ALL patients, due to the abundant antigen stimulation in their bodies, may experience severe adverse reactions within two or three days after CAR-T infusion. Additionally, elderly patients undergoing CAR-T therapy have a higher incidence of central nervous system (CNS) toxicity, especially those with CNS lesions or residual lymphoma, which significantly increases the risk of ICANS. This issue warrants close attention from clinicians.

To improve the safety of CAR-T therapy, the following four strategies should be considered:

1. Comprehensive risk assessment for CRS and ICANS. For patients at high risk of these adverse events, we strongly recommend the early use of steroids for prevention or early treatment. This approach is crucial for interrupting the cascading immune amplification cycle and controlling clinical symptoms in a timely manner. Proper use of steroids can reduce or prevent severe CRS and ICANS in 80% of cases.
2. Rational use of existing IL-6 monoclonal antibodies, including receptor monoclonal antibodies and neutralizing antibodies. We advocate prioritizing neutralizing antibodies to reduce elevated IL-6 levels and block downstream immune activation. This is because the excessive release of pro-inflammatory factors like IL-6 and TNF triggers further immune amplification, exacerbating adverse events. Our preliminary research shows that the use of IL-6 receptor monoclonal antibodies carries a potential risk of IL-6 rebound, with 20% of patients experiencing a tenfold increase in IL-6 levels. For patients at risk of ICANS, caution is advised even when CRS is present.
3. The risks of CRS and ICANS vary significantly between different tumor types and targets. Future efforts should focus on developing a risk assessment system based on patient immune status, clinical baseline characteristics, and CAR-T technical parameters. This would guide the implementation of individualized CRS and ICANS early warning mechanisms for different tumor types and targets, helping clinicians better manage potential adverse events.
4. Strengthen clinical management capabilities by establishing hospital-level multidisciplinary teams (MDT) to promptly address and manage complex cases, ensuring the safety of CAR-T therapy. We should also recognize that existing domestic and international guidelines for managing CAR-T-related adverse reactions have certain limitations and may not always be reasonable. These guidelines should be adapted and referenced based on clinical practice.

Additionally, our team is exploring new clinical research directions regarding infusion dose optimization. CAR-T is currently the only living cell drug, and its scientific dosing in the future may not solely rely on patient body weight or surface area. We have introduced the concept of “effective antigen load (EAD)” and set dose ranges of 105/kg, 106/kg, and 107/kg for B-ALL, lymphoma, and Hodgkin lymphoma patients, respectively. This strategy has shown promising efficacy and safety in our early clinical trials. For B-ALL patients with high EAD, we often reduce the CAR-T infusion dose to maintain efficacy while minimizing adverse reactions.

Dr. Wei Sang Ph.D. in Medicine, Associate Professor, Chief Physician, Ph.D. Supervisor Deputy Director of the Center for Cellular Research and Translational Medicine atThe Affiliated Hospital of Xuzhou Medical University Deputy Director of the Hematology Department and Director of the Lymphoma Ward atThe Affiliated Hospital of Xuzhou Medical University Member of the Lymphocyte Disease Group of the Hematology Branch of the Chinese Medical Association Member of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association Secretary-General of the China EBV-Associated Diseases Working Group Youth Member of the Hematologic Oncology Professional Committee of the Chinese Anti-Cancer Association Member of the Chronic Lymphocytic Leukemia Working Group of the Chinese Anti-Cancer Association Member of the First T-Cell Lymphoma Working Group of the Chinese Anti-Cancer Association Member of the Lymphoma Group of the Hematology Branch of the Geriatrics Society of China Vice Chairperson of the Youth Committee of the Hematology Branch of the Jiangsu Medical Association Vice Chairperson of the Jiangsu Lymphoma Alliance Recipient of the Jiangsu “Six Talent Peaks” and “333” Talent Programs Youth Medical Talent of the “Medical and Educational Strengthening Project” in Jiangsu Province Reviewer for the National Natural Science Foundation of China