Quantifying the Limits of Immunotherapies in Mice and Men

Abstract

AbstractBackgroundCART-cells have demonstrated clinical success for the treatment of multiple different lymphomas and leukaemias. However, comparable clinical efficacy has not been observed for various solid tumours in human clinical trials, despite promising data from murine cancer models. Lower effective CART-cell delivery rates to human solid tumours compared to haematological malignancies in humans and solid tumours in mice might partially explain these divergent clinical outcomes, requiring the development of quantitative methods to calculate effective dosing in the clinic and models.MethodsWe used anatomical and physiological data for human and rodent circulatory systems to calculate the typical value and expected variation of the perfusion of healthy and tumour tissues, and used these to estimate the upper limits of immune cell delivery rates (maximum possible under optimal conditions) across different organs, tumours types and species.ResultsEstimated maximum delivery rates were up to order 10,000-fold greater in mice than humans yet reported CART-cell doses are typically only 10-100-fold lower in mice, suggesting that the effective delivery rates of CART-cells into tumours in clinical trials are far lower than in corresponding mouse models. Estimated delivery rates were compared to published PET data and found to be consistent.ConclusionsThe results suggest that higher effective human doses may be needed to drive efficacy comparable to mouse solid tumour models. These increased doses raise safety and manufacturing concerns. 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.