Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo  

作　　者：ZHIGANG XIA MENGYAO TIAN YUCAI CHENG WENFANG YI ZEFAN DU TIANWEN LI YUCHEN WEN LINDI LI YONG LIU CHUN CHEN 

机构地区：[1]Pediatric Hematology Laboratory,Division of Hematology/Oncology,Department of Pediatrics,The Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen,518107,China [2]Scientific Research Center,The Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen,518107,China

出　　处：《Oncology Research》2024年第6期1109-1118,共10页肿瘤学研究（英文）

基　　金：National Natural Science Foundation of China(No.82370164);Sanming Project of Medicine in Shenzhen(No.SZSM202011004);Shenzhen Science and Technology Innovation Commission(JCYJ20180307150419435 and JCYJ20210324123004011).

摘　　要：Background:Chimeric antigen receptor T(CAR-T)cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies.However,there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T(CAR-T)cell therapy,as well as the optimal timing for CAR-T cell infusion post-chemotherapy.Materials and Methods:We employed cell-derived tumor xenograft(CDX)murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment.Furthermore,transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.Results:Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine,followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy,exerts the most efficacious therapeutic effect in B-cell hematological malignancies.Concurrently,RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism,primarily through the inhibition of key mitochondrial targets,such as C-Jun Kinase enzyme(C-JUN).Conclusion:In summary,the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

关 键 词：CD19 CAR-T B-cell hematologic malignancies Metabolism In vivo 

分 类 号：R733[医药卫生—肿瘤]