Safe and potent anti‐CD19 CAR T‐cells with shRNA‐IL‐6 gene silencing element in patients with refractory or relapsed B‐cell acute lymphoblastic leukemia
Jin‐Feng Ma,
Jia‐Wei Yan,
Mei‐Jing Liu,
Chun‐Long Yan,
Xiao‐Wen Tang,
Hui‐Ying Qiu,
Miao Miao,
Yue Han,
Li‐Min Li,
Li‐Qing Kang,
Nan Xu,
Zhou Yu,
Jing‐Wen Tan,
Hong‐Jia Zhu,
Xu Jia,
Zhi‐Zhi Zhang,
Miao Wang,
Hai‐Ping Dai,
Lei Yu,
Sheng‐Li Xue,
De‐Pei Wu,
Wen‐Jie Gong
Affiliations
Jin‐Feng Ma
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Jia‐Wei Yan
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Mei‐Jing Liu
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Chun‐Long Yan
Department of Hematology Jining No. 1 People's Hospital Jining China
Xiao‐Wen Tang
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Hui‐Ying Qiu
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Miao Miao
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Yue Han
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Li‐Min Li
Department of Hematology Southern University of Science and Technology Hospital Shenzhen China
Li‐Qing Kang
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Nan Xu
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Zhou Yu
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Jing‐Wen Tan
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Hong‐Jia Zhu
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Xu Jia
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Zhi‐Zhi Zhang
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Miao Wang
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Hai‐Ping Dai
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Lei Yu
Research and Development Department Shanghai Unicar‐Therapy Bio‐Medicine Technology Co., Ltd. Shanghai China
Sheng‐Li Xue
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
De‐Pei Wu
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Wen‐Jie Gong
National Clinical Research Center for Hematologic Diseases Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University Suzhou China
Abstract Severe cytokine release syndrome (sCRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)‐cell therapy. We designed a novel anti‐CD19 CAR (ssCART‐19) with a small hairpin RNA (shRNA) element to silence the interleukin‐6 (IL‐6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART‐19 with common CAR T‐cells (cCART‐19) in relapsed/refractory B‐cell acute lymphoblastic leukemia (r/r B‐ALL). Among 87 patients, 47 received ssCART‐19 and 40 received cCART‐19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART‐19 group versus 37.5% (15/40) in the cCART‐19 group (p = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART‐19 group (all grade 1) compared to 15% (2/40) of the cCART‐19 group. Patients in the ssCART‐19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART‐19 and 85% (34/40) for cCART‐19 (p = 0.999). With a median follow‐up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART‐19 and 13.6% for cCART‐19 (p = 0.33). Median overall survival was 37.17 months for ssCART‐19 and 32.93 months for cCART‐19 (p = 0.40). Median progression‐free survival was 24.17 months for ssCART‐19 and 9.33 months for cCART‐19 (p = 0.23). These data support the safety and efficacy of ssCART‐19 for r/r B‐ALL, suggesting its potential as a promising therapy.
