Engineering better chimeric antigen receptor T cells
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Experimental Hematology & Oncology Open Access
REVIEW
Engineering better chimeric antigen receptor T cells Hao Zhang1, Pu Zhao1 and He Huang2*
Abstract CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study. Keywords: Chimeric antigen receptor T cells, Acute lymphoblastic leukemia, Relapse, Persistence, Differentiation, Exhaustion Background In recent years, chimeric antigen receptor T cells (CAR T) emerged as one of the most promising approach in cancer treatment [1]. The most impressive responses have been achieved in patients with B cell malignancy, especially in refractory or relapsed B acute lymphoblastic leukemia (B-ALL) treated by CAR T cells targeting CD19 with the complete remission (CR) rate reaching 90% [2–5]. However, ~ 30–50% of patients experienced leukemia relapse, the majority relapsed within 1 year after CAR T cells therapy [6], and with prolonged followup, the relapse rate may be much higher. Disease relapse *Correspondence: [email protected] 2 Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, No. 79 Qingchun Road, Hangzhou, China Full list of author information is available at the end of the article
following CAR T cell therapy can be categorized into two major patterns: target antigen loss relapse or antigenpositive relapse. The mechanisms associated with loss of CD19 after CART cells therapy include the deletion or mutation of CD19 gene in leukemic cells [7, 8], abnormal CD19 RNA splicing because of decreased expression of splicing factor SRSF3 [8], leukemia lineage transformation caused by transcription factors PAX5 and EBF1 associated reprogramming of the pre-B cel
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