On June 14-17, 2018, the 23rd EHA conference was held in Stockholm, Sweden, and the key studies in the field of hematology were presented. In the conference, Dr. Jing PAN from Beijing Boren Hospital gave an oral presentation on the “efficacy and safety of CD22-CAR-T cells in 15 children with refractory and relapsed B-cell acute lymphocytic leukemia”, which attracted a great attention of the conference. [Oncology Information] The author of the study, Dr. Jing PAN from Beijing Boren Hospital, was invited to make an on-site interpretation of the study.
Jing PAN, Associate Chief Physician, Master of Medicine
Associate Chief Physician, Master of Medicine in Department of Pediatric Hematology, Beijing Boren Hospital. She has been engaged in the clinical work in the Department of Pediatric Hematology for many years and has accumulated rich clinical and scientific research experience. She has accumulated rich clinical experience in the chemotherapy for leukemia in children, congenital bone marrow failure syndrome in children and CAR-T cell immunotherapy and treated more than 10 children with refractory and relapsed acute B-lymphocytic leukemia with CAR-T therapy every year, and the efficacy is at an advanced level internationally.
Interview with Dr. Jing PAN
Academic research team
Our team is from Beijing Boren Hospital. Although the hospital is very new, we are an older team led by Director Chunrong TONG. Since 2015, our team has been engaged in CAR-T research. At the beginning, the number of cases was small. In July 2015, we started the clinical study on CD19 CAR-T, and the relevant results had been accepted and published in Leukemia.
Efficacy of CD22 CAR-T cells
A total of 15 children with ALL were included in this study, all of whom were resistant to chemotherapy, and four of them relapsed after hematopoietic stem cell transplantation. Fourteen patients had no response to CD19 CAR-T therapy or relapsed after treatment. Except 1 patient, 14 patients had very low expression of CD19 in leukemia cells after relapse, so they could not be treated with CD19 CAR-T. However, we found that the common feature of this group of patients was that CD22 antigen was expressed in leukemia cells, so we intended to use CD22 CAR-T for treatment. The final study results showed that CD22 CAR-T cell therapy had a high remission rate, with a complete remission (CR) rate of 80%, and one patient had partial remission (PR), so the overall response rate was 86.7%.
Safety of CD22 CAR-T Cell Therapy
During the use of CD22 CAR-T cells, people were more concerned about its side effects, i.e., safety issues. In our study, the cytokine storm syndrome (CRS) was only at about grade 1 in the treatment of all 15 patients, so they were in a very safe state. No serious central nervous system toxicity was observed during the treatment. Moreover, we compared the risk of CAR-T cell therapy between transplanted patients and non-transplanted patients and found that transplantation had no significant effect on side effects, so the safety of CD22 CAR-T cell therapy was consistent in both groups of patients.
Treatment After Response to CD22 CAR-T Cells
From the long-term observation data, we recommend hematopoietic stem cell transplantation for such patients. The transplantation team led by Director Tong WU is very strong. The patients in this study underwent transplantation about two months after CAR-T therapy, and our transplantation team is highly skilled. This may also explain why the patients in this study had a very high long-term survival rate. In this EHA conference, it was reported internationally that the effect of transplantation after CAR-T therapy was not satisfactory, so transplantation was not recommended, but our view has always been that bridging transplantation is a good choice. In this abstract, all patients were followed up for about 3 months, and the long-term survival rate was 91.7%. Until now, most patients were in disease-free survival state. Can CD22 CAR-T cell therapy really help such patients? In other words, is there really a survival benefit? At present, it is necessary to expand the number of cases, accumulate a large amount of data and prolong the follow-up for verification.
Key Factors for The Success of This Study
Questions concerned about by foreign media: Why is this study so successful? I think there are three main factors.
First, design of CAR. We have been working with Professor Hongsheng ZHANG's team, and its designed CAR has the characteristics of high affinity and good safety.
Second, culture of CAR-T cells. All operations after the acquisition of CAR were completed in Beijing Boren Hospital. In addition to the CAR design described above, the second key factor is the culture of CAR-T cells. Biping DENG’s team in our clinical laboratory has done a good job in cell culture, and the number and quality of CAR-T cells provided were guaranteed.
Furthermore, clinical aspects. When the foreign media mentioned whether patients outside the clinical trial achieved good efficacy, the answer is yes, because some patients progressed very quickly, and if they followed the clinical trial protocol step by step, the treatment might be delayed, so they were not included in the clinical trial. We will cooperate and communicate with the laboratory on CAR culture time, pretreatment plan, etc.; evaluate each patient, including early evaluation of whether serious cytokine release syndrome (CRS) may occur, and dealing with it in a timely manner. In our study, the severity of CRS was low, mainly because clinicians had rich clinical experience. Overall, the strength of the whole team made the results very impressive.
Oral presentation: “Efficacy and safety of CD22-CAR-T cells in 15 children with refractory and relapsed B-cell acute lymphocytic leukemia
Many patients with relapsed/refractory (R/R) B-cell acute lymphocytic leukemia (B-ALL) developed progression of disease within 1 year after successful treatment with CD19 chimeric antigen receptor T (CAR-T) cells, and most of them had no response when they received CD19 CAR-T cell therapy again. Even if patients with R/R B-ALL received allogeneic hematopoietic stem cell transplantation (allo-HCT), the relapse rate was still high. Therefore, it is urgent to explore new treatment modes and methods.
To evaluate the efficacy and safety of novel humanized CD22-CAR-T cells in children with R/R B-ALL.
From July 6, 2017 to January 8, 2018, 15 children with R/R B-ALL who received CD22 CAR-T cell therapy were admitted to Beijing Boren Hospital. The median age of the patients was 8 years old (range: 2-18 years old). The median duration of disease was 21 months (range: 5-84 months). Of the 15 patients included in this study, 4 relapsed after allo-HCT and 11 relapsed after chemotherapy. Fourteen patients had previously received CD19 CAR-T cell therapy. When one patient relapsed, CD19 was weakly expressed in leukemia cells. Of the 15 patients, 11 were manifested as hematologic relapse, and the median percentage of blasts in bone marrow (BM) was 42 (5-95.5)%; 2 were detected as positive minimal residual disease (MRD) by flow cytometry (FCM); 2 were manifested as extramedullary diseases (EMDs). CD22 was expressed in leukemia cells of all patients.
This study used a lentiviral vector system carrying a second-generation CAR comprising of anti-CD22 scFV, 4-1BB costimulatory molecules and CD3z signaling domain derived from humanized CD22 antibody. Peripheral blood mononuclear cells were collected from all patients for preparation of CAR-T cells, and the preparation was completed on days 7-8. The median dose of CD22 CAR-T cell infusion in non-transplanted patients and transplanted patients was 8.2 (0.5-34.7) x 105/kg and 0.9 x 105/kg, respectively. Amplification of CD22 CAR-T cells and cytokine release syndrome (CRS) were closely monitored after infusion. At 30 days after infusion, the efficacy was evaluated by BM examination, and EMDs were evaluated by imaging (ultrasound, MRI and PET-CT). Long-term follow-up of all patients was performed to analyze the factors that affected the outcomes.
The peak amplification of CAR-T cells (3.2%-71.7% of CD3+ cells) was detected at 11±1.8 days. At the efficacy evaluation at 30 days, 13 of the 15 patients had response to the treatment. Of the 11 patients with hematologic relapse, 10 achieved CR or CR with incomplete recovery (CRi) of blood cell count, and 9 of them showed negative MRD in FCM. Of the 2 patients who had positive MRD at the beginning, 1 turned to negative MRD in FCM. Of the 2 patients with EMDs, 1 achieved CR and 1 achieved partial response (PR) (tumor size: reduced from 10.0 × 5.3 × 5.9 cm to 6.2 × 2.3 × 3.1 cm). Two patients had no response to CD22-CAR-T treatment, and their cell line cells still strongly expressed CD22 antigen. All patients developed only mild to moderate CRS (grade 0-2), and 2 patients developed grade 1 neurotoxicity. There was no significant difference in CRS between patients who received and those who did not receive allo-HCT (P=0.41). The median follow-up time was 108 (46-199) days, and 6 patients completed bridging allo-HCT after CD22-CAR-T cell therapy. Of the 12 patients who achieved CR/CRi, 11 achieved progression-free survival (PFS), and 1 relapsed at 50 days. All patients were followed up to now, and most patients maintained disease-free survival.
The results of this study show that CD22 CAR-T cell therapy is a relatively effective and safe treatment for children with R/R B-ALL, and it may be particularly suitable for patients who previously have response to CD19 CAR-T cell therapy but no response to reuse after relapse. Currently, it is still necessary to further prolong the follow-up period to determine the long-term outcome of CD22 CAR-T cell therapy and to further determine whether allo-HCT can reduce the relapse rate after CD22 CAR-T cell therapy.