Early induction of cytokine release syndrome by rapidly generated CAR T cells in preclinical models.

Autor:	Jamali A; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Ho N; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.; Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany., Braun A; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Adabi E; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany., Thalheimer FB; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.; Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany.; Hematology, Cell and Gene Therapy (HZG), Paul-Ehrlich-Institut, Langen, Germany., Buchholz CJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany. Christian.Buchholz@pei.de.; Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany. Christian.Buchholz@pei.de.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Christian.Buchholz@pei.de.
Jazyk:	angličtina
Zdroj:	EMBO molecular medicine [EMBO Mol Med] 2024 Apr; Vol. 16 (4), pp. 784-804. Date of Electronic Publication: 2024 Mar 21.
DOI:	10.1038/s44321-024-00055-9
Abstrakt:	Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector exposure, are in focus of current investigations. Their impact on the incidence and severity of CRS has been poorly explored. Here, we evaluated CD19-specific stCAR T cells in preclinical models. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and potent release of CRS-related cytokines (IL-6, IFN-γ, TNF-α, GM-CSF, IL-2, IL-10). When administered to NSG-SGM3 mice, stCAR T cells, but not conventional CAR T cells, induced severe acute adverse events within 24 h, including hypothermia and weight loss, as well as high body scores, independent of the presence of tumor target cells. Human (IFN-γ, TNF-α, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines, typical for severe CRS, were systemically elevated. Our data highlight potential safety risks of rapidly manufactured CAR T cells and suggest NSG-SGM3 mice as sensitive model for their preclinical safety evaluation. (© 2024. The Author(s).)
Databáze:	MEDLINE
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