Generation and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy

Jingjing Ren (), Xiaofeng Liao (), Julia M. Lewis, Jungsoo Chang, Rihao Qu, Kacie R. Carlson, Francine Foss and Michael Girardi ()
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Jingjing Ren: Yale School of Medicine
Xiaofeng Liao: Yale School of Medicine
Julia M. Lewis: Yale School of Medicine
Jungsoo Chang: Yale School of Medicine
Rihao Qu: Yale School of Medicine
Kacie R. Carlson: Yale School of Medicine
Francine Foss: Yale School of Medicine
Michael Girardi: Yale School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Current treatments for T cell malignancies encounter issues of disease relapse and off-target toxicity. Using T cell receptor (TCR)Vβ2 as a model, here we demonstrate the rapid generation of an off-the-shelf allogeneic chimeric antigen receptor (CAR)-T platform targeting the clone-specific TCR Vβ chain for malignant T cell killing while limiting normal cell destruction. Healthy donor T cells undergo CRISPR-induced TRAC, B2M and CIITA knockout to eliminate T cell-dependent graft-versus-host and host-versus-graft reactivity. Second generation 4-1BB/CD3zeta CAR containing high affinity humanized anti-Vβ scFv is expressed efficiently on donor T cells via both lentivirus and adeno-associated virus transduction with limited detectable pre-existing immunoreactivity. Our optimized CAR-T cells demonstrate specific and persistent killing of Vβ2+ Jurkat cells and Vβ2+ patient derived malignant T cells, in vitro and in vivo, without affecting normal T cells. In parallel, we generate humanized anti-Vβ2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) by Fc-engineering for NK cell ADCC therapy.

Date: 2024
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DOI: 10.1038/s41467-024-44786-2

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