Comparative Anatomical Limits of CART-Cell Delivery to Tumours in Mice and Men

CART (Chimeric Antigen Receptor T)-cells are approved for treatment of several leukaemia and lymphoma indications. However, this therapeutic modality has not delivered comparable clinical efficacy for solid tumour indications despite promising preclinical outcomes in mouse solid tumour models. Lower rates of effective CART-cell delivery to solid tumours in humans as compared to human haematological malignancies and/or solid tumours in mice might partially explain these divergent outcomes. As the initial delivery of CART-cells to tumour tissue is mediated by the circulatory system, we developed models of the human, rat and mouse circulatory systems. Model structure and parameterisation were informed by an extensive body of published comparative anatomical and physiological studies and associated experimental data. Models were used to estimate the species-dependent upper limit and variation of delivery rates of blood borne immune cells, such as T- and NK cells, to tumour tissue across different organs and species. Large cross-species differences in absolute delivery rates to organs were identified. Estimated maximum delivery rates were up to 10,000-fold greater in mice than humans, yet reported administered CART-cell doses were typically only 10-100 times lower in mice. This suggests that higher human CART-doses may be needed to drive efficacy comparable to that observed in preclinical solid tumour mice models. Accordingly, we posit that a more quantitative analysis of species- and organ-specific immune cell delivery rates and how they may be pharmacologically optimised will be key to unlocking the potential of engineered T-cells for solid tumours.