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Quantifying the limits of CAR T-cell delivery in mice and men

Brown, Liam V., Gaffney, Eamonn A., Ager, Ann, Wagg, Jonathan and Coles, Mark C. 2021. Quantifying the limits of CAR T-cell delivery in mice and men. Journal of the Royal Society Interface 18 (176) , 20201013. 10.1098/rsif.2020.1013

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Abstract

CAR (Chimeric Antigen Receptor) T cells have demonstrated clinical success for the treatment of multiple lymphomas and leukaemias, but not for various solid tumours, despite promising data from murine models. Lower effective CAR T-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent outcomes. We used anatomical and physiological data for human and rodent circulatory systems to calculate the typical perfusion of healthy and tumour tissues, and estimated the upper limits of immune cell delivery rates across different organs, tumour types and species. Estimated maximum delivery rates were up to 10 000-fold greater in mice than humans yet reported CAR T-cell doses are typically only 10–100-fold lower in mice, suggesting that the effective delivery rates of CAR T cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were found to be consistent with published positron emission tomography data. Results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models, and that lower doses should be tested in mice. We posit that quantitation of species and organ-specific delivery and homing of engineered T cells will be key to unlocking their potential for solid tumours.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Royal Society, The
ISSN: 1742-5662
Date of First Compliant Deposit: 28 April 2021
Date of Acceptance: 4 February 2021
Last Modified: 06 Oct 2021 13:41
URI: https://orca.cardiff.ac.uk/id/eprint/140831

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