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

• Published in: bioRxiv
• Main Authors: Ho, Naphang, Jamali, Arezoo, Braun, Angela, Adabi, Elham, Thalheimer, Frederic B., Buchholz, Christian J.
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Laboratory 12.11.2022
• Edition: 1.1
• Subjects: Pharmacology and Toxicology; NSG-SGM3 mouse model; CRS model; Cytokine release syndrome; CAR T cell; myeloid cells; rapid manufactured CAR T cell; preclinical safety model; lentiviral vector
• ISSN: 2692-8205
• DOI: 10.1101/2022.11.12.515207

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-γ, TNF-α, 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-α, 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.