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Updated: Nov 15, 2025
Author Spotlight: Enhancing CAR-T Cell Function in Syngeneic Tumor Models
Published on: February 2, 2024
Quantifying the limits of CAR T-cell delivery in mice and men
Liam V Brown1,2, Eamonn A Gaffney1, Ann Ager3
1Wolfson Centre For Mathematical Biology, Mathematical Institute, University of Oxford, Oxford, UK.
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.
Insights
Chimeric antigen receptor (CAR) T-cell therapy shows promise for solid tumors but faces delivery challenges. This study suggests higher human doses may be needed, informed by species-specific circulatory system analysis.
Area of Science:
- Immunotherapy
- Oncology
- Translational Medicine
Background:
- Chimeric antigen receptor (CAR) T-cell therapy is effective against blood cancers but less so for solid tumors.
- Discrepancies in efficacy between mouse models and human clinical trials for solid tumors are observed.
Purpose of the Study:
- To investigate the impact of circulatory system differences on CAR T-cell delivery to solid tumors across species.
- To provide a quantitative basis for optimizing CAR T-cell dosing in human and preclinical solid tumor studies.
Main Methods:
- Utilized anatomical and physiological data of human and rodent circulatory systems.
- Calculated tissue perfusion and estimated maximum immune cell delivery rates for various organs and tumor types.
- Compared estimated delivery rates with reported CAR T-cell doses and positron emission tomography data.
Main Results:
- Estimated maximum CAR T-cell delivery rates were up to 10,000-fold higher in mice than in humans.
- Reported CAR T-cell doses in mice are only 10-100-fold lower than in humans, indicating significantly lower effective delivery in clinical settings.
- Estimated delivery rates correlated with published positron emission tomography data.
Conclusions:
- Effective CAR T-cell delivery rates to human solid tumors are substantially lower than in mouse models.
- Higher effective CAR T-cell doses may be required for efficacy in human solid tumors.
- Quantifying species- and organ-specific delivery is crucial for advancing CAR T-cell therapy for solid tumors.
