CAR-T cell therapy is currently a hot research topic in the field of hematology, but how to transform the clinical issues of CAR-T cell therapy into scientific research questions remains a challenge for many clinicians. From January 26th to 28th, 2024, the “Chinese Society of Clinical Oncology (CSCO) Leukemia Committee, Lymphoma Committee, and Myeloma Preparatory Committee Work Meeting and 2024 CSCO Hematology, Lymphoma, and Myeloma Academic Conference” was grandly held in the beautiful city of Haikou. At the conference, Professor Kailin Xu , Director of the Hematology Institute at Xuzhou Medical University, shared his experience and insights on transforming clinical issues of CAR-T cell therapy into scientific research questions from five aspects under the topic “From Clinical to Scientific Questions—Entry Points for CAR-T Clinical Research.” His insights are of great reference and significance for conducting related research, and are specially compiled as follows.
Clinical Issue 1
The short-term efficacy of CAR-T cell therapy is encouraging, but the long-term efficacy is not satisfactory. How can the long-term efficacy be improved?
One important reason for the poor long-term efficacy of CAR-T cell therapy is that cancer stem cells are not completely eradicated. In the treatment of Multiple Myeloma (MM), B-cell maturation antigen (BCMA) is a very good target, and related drugs have already been marketed in China. So, how can we improve its long-term efficacy? As we know, after being stimulated by antigens, B-cells differentiate into plasma cells and produce antibodies. In this process, although a lot of CD19 antigen is lost and rarely expressed on plasma cells, this small expression may represent the early stages of myeloma cells, namely myeloma-like stem cells. Facing such a clinical issue, how to design a clinical approach to improve its long-term efficacy, we consider combining anti-BCMA and anti-CD19 CAR-T cells for dual-target treatment. The research results have been published in Lancet Haematol and J Clin Oncol in 2019 and 2022, respectively:
In terms of short-term efficacy: among the enrolled 62 patients, the objective response rate (ORR) reached 92%; the rate of stringent complete response/complete response (sCR/CR) exceeded 60%; the minimal residual disease (MRD) negativity rate reached 77% (43/56).
Regarding the more concerned long-term efficacy: the median duration of response (DOR) was as long as 20.3 months, indicating very good long-term efficacy. In addition, the median progression-free survival (PFS) reached 18.3 months, which is currently the best indicator of long survival following CAR-T cell therapy for MM, with the median overall survival (OS) not yet reached. Among patients achieving CR or better, the 12-month PFS rate was 89%, and the OS rate was 92%. Moreover, comparative analysis revealed that dual-target anti-BCMA+CD19 CAR-T cell therapy significantly outperformed single-target anti-BCMA CAR-T cell therapy in terms of PFS and OS.
Kaplan-Meier analysis of Duration of Response (DOR)
Kaplan-Meier analysis of Progression-Free Survival (PFS) and Overall Survival (OS)
Another design that can improve long-term efficacy is the use of humanized CAR-T and fully human CAR-T. The Hematology Institute of Xuzhou Medical University is one of the earliest centers in China to introduce humanized CAR-T. Currently, the commercial CAR-T used in clinics is still primarily mouse-derived CAR-T. Humans have a natural immune rejection to the mouse-derived CAR-T’s single-chain variable fragment, which may be one aspect leading to poor long-term efficacy. Our use of humanized CAR-T to treat relapsed/refractory (R/R) acute B lymphoblastic leukemia (B-ALL) can achieve a remission rate of up to 90%; after bridging transplantation, the 2-year progression-free survival (PFS) rate can reach over 80%; it was also found that the presence of anti-drug antibodies (ADAs) is related to relapse.
Clinical Issue 2
ICANS is a major complication of CAR-T cell therapy. What is the efficacy and safety of CNS B-ALL treatment?
For B-ALL with central nervous system (CNS) involvement, there is a lack of effective treatment options, and the treatment outcomes are not satisfactory. After the advent of CAR-T, one question we considered was whether CAR-T cells could cross the central barrier and, once in the CNS, what would be the effect on CNS B-ALL? Another question is that CAR-T cell therapy has two relatively special complications: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). So, is the incidence or severity of ICANS higher or more severe in CNS B-ALL patients? To address this, we led a collaborative effort to compile and analyze data from several hospitals in China (including Tianjin First Central Hospital, The First Affiliated Hospital of Zhejiang University Medical College, Tongji Hospital affiliated with Tongji University Shanghai, and Tongji Hospital affiliated with Huazhong University of Science and Technology). The related work was published in Blood in 2022.
The study enrolled 48 patients. The results showed: an ORR of 88% in the bone marrow and a remission rate of 85% in the CNS, with little difference between the two; the bridging treatment group had better efficacy; the median OS reached 16.0 months, and the median event-free survival (EFS) reached 8.7 months. This suggests that CAR-T cell therapy can cross the blood-brain barrier into the CNS and can have a good therapeutic effect. Additionally, in terms of central nervous toxicity, the incidence of encephalopathy was 22.9%, with a ≥ grade 3 incidence of 8.3%. Therefore, the incidence of central nervous toxicity was not as high as imagined, and it was not as daunting to manage. It is believed that in the future, with the optimization of CAR-T structure, further reduction of adverse events, especially the reduction in price, CAR-T cell therapy will show great potential in CNS B-ALL.
Remission Rate and Subgroup Analysis
Clinical Issue 3
China is a populous country with a high need for attention to HBV-related infections. What is the impact of CAR-T cell therapy on HBV reactivation and liver function?
Regarding the adverse events that may arise from immunotherapy, China is a major country affected by hepatitis B virus (HBV) related infections. So, does CAR-T cell therapy have any impact on HBV or liver function? It’s known that with CD20 monoclonal antibody treatment for diffuse large B-cell lymphoma, very few patients experience HBV reactivation, and since CAR-T immunotherapy is more intense than CD20 monoclonal antibodies, could it pose similar issues? We summarized the outcomes of 70 patients, among which 12 had chronic HBV infection, 29 had a history of HBV infection, and 29 had no evidence of any HBV infection. The study results were published in Leukemia in 2020. The results showed that 2 out of 12 patients with chronic HBV infection and 1 out of 29 patients with a history of HBV infection experienced HBV reactivation, while none of the 29 patients without any HBV infection experienced new HBV infection. This indicates that it is very necessary to start preventive anti-HBV treatment before CAR-T therapy for patients with chronic HBV infection; patients with a history of infection should also be closely monitored, and if HBV reactivation occurs, anti-HBV treatment should be administered. Additionally, the study found that chronic or previous HBV infection does not affect the efficacy of CAR-T cell therapy, nor does it increase the incidence or severity of CRS and neurotoxicity.
Clinical Issue 4
For patients with multiple myeloma (MM) who relapse or progress after remission from CAR-T cell therapy, how should the next step in treatment be chosen?
What to do if there is a relapse after CAR-T cell therapy? This is a common question. Taking multiple myeloma (MM) as an example, we conducted a Phase II clinical trial of anti-GPRC5D CAR-T therapy for R/R MM, and the results have been published in J Clin Oncol. A total of 33 patients were enrolled, with an ORR of 91%, similar to the efficacy of currently marketed anti-BCMA CAR-T therapies; the sCR/CR rate also reached 63%, making GPRC5D a very competitive target following BCMA. Of particular interest were 9 patients who had failed or progressed after BCMA therapy, including 2 patients who had repeatedly received anti-BCMA CAR-T cell infusions but did not respond to the last one. These 2 patients achieved a CR and partial remission (PR), respectively, after receiving anti-GPRC5D CAR-T therapy. The remaining 7 patients were those who relapsed or progressed after anti-BCMA CAR-T cell therapy. Overall, after receiving anti-GPRC5D CAR-T cell therapy, 4 patients achieved CR, 2 achieved very good PR (VGPR), and 3 achieved PR.
Response and Toxicity of Anti-GPRC5D CAR-T Cells in Patients Previously Treated with Anti-BCMA CAR-T Cell Therapy
Regarding safety, among the 33 patients observed, the incidence of Cytokine Release Syndrome (CRS) was 76%, with no grade 3 CRS; the rate of neurotoxicity was also low, with one case each of grade 2 and grade 3 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), and one case of grade 3 headache. However, there were some specific complications mainly caused by off-target effects, which did not cause significant discomfort to the patients, such as nail loss leading to onycholysis, occurring in 30% of cases. However, this was not a major issue as the old nails fell off and new nails grew back. For patients relapsing after anti-BCMA CAR-T therapy, switching to a new target CAR-T provides an additional option. As mentioned earlier, our center’s anti-BCMA CAR-T therapy achieved a median Progression-Free Survival (PFS) of 18.3 months. If relapsed patients receive new target CAR-T therapy, they may gain more opportunities for prolonged survival.
Clinical Issue 5
CAR-T, as an adoptive cellular immunotherapy, with the most common targets being BCMA and CD19, which respectively act on plasma cells and B cells, what impact does it have on the reconstruction of humoral immunity?
The targeting of plasma cells by BCMA, GPRC5D, or B cells by CD19 all affect humoral immunity. Would these impacts cause serious consequences for the patients? We observed the dynamics of peripheral blood B cells and bone marrow plasma cells after anti-BCMA CAR-T treatment. The results showed that all patients experienced B cell aplasia (BCA). B cell counts dropped to their lowest median 7 days after CAR-T infusion; 2 months post-CAR-T infusion, B cell counts remained consistently low. It took a median of 97 days to return to baseline levels and a median of 177 days to normalize. Normal plasma cells were first detected at a median of 212 days. However, this impact on humoral immunity was not severe and was manageable. Clinically, intravenous immunoglobulin supplementation can be used to safely navigate patients through the period of immunosuppression.
Dynamics of B Cell Recovery in Patients Treated with Anti-BCMA CAR-T Cell
Dynamics of Serum IgG, IgM, and IgA Recovery in Patients Treated with Anti-BCMA CAR-T Cells
Professor Kailin Xu
Professor Kailin Xu is the Director of the Hematology Institute at Xuzhou Medical University, holding a doctoral degree, a second-level professorship, and a doctoral supervisor position. He is also the Director of the Jiangsu Provincial Institute of Hematopoietic Stem Cells and the Director of the Hematopoietic Stem Cell Transplantation Center at Xuzhou Medical University. He has been a member of the ninth and tenth committees of the Hematology Branch of the Chinese Medical Association, serving as the Deputy Leader of the Experimental Diagnosis Group. Professor Xu is an executive member of the Hematology Physician Branch of the Chinese Medical Doctor Association, the former Director of the Jiangsu Provincial Hematology Branch, and the current President of the Hematology Physician Branch of the Jiangsu Medical Doctor Association. He is an expert for both the initial and final review panels for the National Natural Science Foundation and has been recognized as a middle-aged expert with outstanding contributions by the Ministry of Health and Jiangsu Province, enjoying a special government allowance from the State Council.
As the principal investigator, he has undertaken more than 20 scientific research projects, including one key project of the National Natural Science Foundation, one special project on CAR-T cell therapy, eight general projects, and more than ten provincial and ministerial-level projects. He has published over 180 papers, including 90 SCI-indexed papers in journals such as JCO, Blood, Lancet Haematology, Leukemia, Haematologica, and Am J Hematol. As the first awardee, he has received 16 scientific and technological achievement awards, including two second prizes of the Scientific and Technological Achievement Award of the Ministry of Education for Colleges and Universities, one third prize of the Chinese Medical Science and Technology Award, and one second prize for Scientific and Technological Progress.
