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Construction and functional characterization of a fully human anti-CD19 chimeric antigen receptor (huCAR)-expressing primary human TÂ cells
Authors
K. Alishah
S.A.H. Emami
+8 more
K. Fallah Mehrjardi
J. Hadjati
L. Jafarzadeh
A. Jamali
E. Masoumi
H.R. Mirzaei
F. Noorbakhsh
B.G. Till
Publication date
1 January 2019
Publisher
Abstract
Although remarkable results have been attained by adoptively transferring T cells expressing fully murine and/or humanized anti-CD19 chimeric antigen receptors (CARs) to treat B cell malignancies, evidence of human anti-mouse immune responses against CARs provides a rationale for the development of less immunogenic CARs. By developing a fully human CAR (huCAR), these human anti-mouse immune responses are likely eliminated. This, perhaps, not only increases the persistence of anti-CD19 CAR T cells�thereby reducing the risk of tumor relapse�but also facilitates administration of multiple, temporally separated doses of CAR T cells to the same recipient. To these ends, we have designed and constructed a second-generation fully human anti-CD19 CAR (or huCAR19) containing a fully human single-chain variable fragment (ScFv) fused with a CD8a hinge, a 4-1BB transmembrane domain and intracellular T cell signaling domains of 4-1BB and CD3z. T cells expressing this CAR specifically recognized and lysed CD19 + target cells produced cytokines and proliferated in vitro. Moreover, cell volume data revealed that our huCAR construct cannot induce antigen-independent tonic signaling in the absence of cognate antigen. Considering our results, our anti-CD19 huCAR may overcome issues of transgene immunogenicity that plague trials utilizing CARs containing mouse-derived ScFvs. These results suggest that this huCAR19 be safely and effectively applied for adaptive T cell immunotherapy in clinical practice. © 2018 Wiley Periodicals, Inc
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eprints Iran University of Medical Sciences
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Last time updated on 01/12/2020