Early induction of severe cytokine release syndrome by rapidly generated CAR T cells in a preclinical mouse model

Ho, N.; Jamali, A.; Braun, A.; Adabi, E.; Thalheimer, F.; Buchholz, C. J.

doi:10.1101/2022.11.12.515207

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bioRxiv · 10.1101/2022.11.12.515207

Early induction of severe cytokine release syndrome by rapidly generated CAR T cells in a preclinical mouse model

Ho, N.·Jamali, A.·Braun, A.·Adabi, E.·Thalheimer, F.·Buchholz, C. J.

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Abstract

Chimeric antigen receptor (CAR) T cells have emerged as effective strategy against B cell malignancies. Since the long manufacturing process limits patient accessability, short-term (st) CAR T cells are under investigation. Here, we evaluated CD19-CAR T cells 24 hours after exposure to lentiviral vectors. In co-culture with tumor cells and monocytes, stCAR T cells exhibited anti-tumoral activity and strong release of CRS-relevant cytokines (IL-6, IFN-{gamma}, TNF-, GM-CSF, IL-2, IL-10). When administered into tumor engrafted NSG-SGM3 mice, severe acute adverse events encompassing high body scoring, temperature and weight drop arised rapidly within 24 hours. Human (IFN-Y, TNF-, IL-2, IL-10) and murine (MCP-1, IL-6, G-CSF) cytokines typical for severe cytokine release syndrome (CRS) were systemically elevated. Our data highlight potential safety risks of CAR T cells manufactured within short time and suggest simple models for their preclinical safety evaluation.

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Ho, N., Jamali, A., Braun, A., Adabi, E., Thalheimer, F., Buchholz, C. J.. 2022-11-12. Early induction of severe cytokine release syndrome by rapidly generated CAR T cells in a preclinical mouse model. https://doi.org/10.1101/2022.11.12.515207

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