Applying population mechanistic modelling to find determinants of chimeric antigen receptor T-cells dynamics in month-one lymphoma patients.

Background: Chimeric antigen receptor (CAR) T-cells have been utilized for the treatment of several malignancies, including Non-Hodgkin lymphomas. A myriad of product- and patient-specific factors determines the extent of patient response, and determining which are most impactful requires analysis of clinical data. Methods: We used population-level ordinary differential equation models to fit clinical flow cytometry and tumour biopsy data from the TRANSCEND-NHL-001 (NCT02631044) study [1]. We analyzed the impact of lymphodepletion, CAR T-cell phenotypes, and other factors on CAR T-cell dynamics for 30 days after infusion. Results: We quantified the relative contribution of antigen-dependent and independent sources of proliferation on CAR T-cell dynamics, finding that both make a large contribution and that antigen-independent proliferation was highly correlated with patient IL-15 and IL-7 blood concentrations. The proportion of CAR T-cells in naïve, memory, or effector cells was found to have a limited impact on CAR T-cell dynamics, compared with lymphodepletion and tumour burden. Conclusions: This study shows how models can be used to link endogenous T-cells, CAR T-cells, and their phenotypes, and may be useful for determining whether a given patient may be responding poorly to treatment, by observing the dynamics of their endogenous T-cells. The framework we developed can be utilized for other CAR T constructs and indications, to test product alterations or biological hypotheses at the population level.