TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy.

JCI Insight
Jane RasaiyaahWaseem Qasim

Abstract

T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3ε CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRαβ/CD3 complex. Only transduction after disrupting assembly of TCRαβ/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3ε was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/mu...Continue Reading

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Citations

Jan 12, 2019·American Journal of Hematology·Waseem Qasim
Jan 5, 2020·Nature Reviews. Drug Discovery·S DepilL Poirot
Dec 18, 2019·Briefings in Functional Genomics·Guillermo Ureña-BailénMarkus Mezger
Oct 6, 2020·Frontiers in Immunology·Francesco ManfrediEliana Ruggiero
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Dec 5, 2020·Hematology·Adam J Lamble, Rebecca Gardner
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May 27, 2021·Leukemia·Christos GeorgiadisWaseem Qasim
Jul 30, 2021·Stem Cell Research & Therapy·Ehsan RazeghianFarhad Motavalli Khiavi
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Oct 22, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tara Murty, Crystal L Mackall

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Methods Mentioned

BETA
PCR
flow cytometry
FCS

Clinical Trials Mentioned

NCT02808442
NCT03190278

Software Mentioned

3CAR
GraphPad Prism
GeneArt

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