Thesis title: Pharmacokinetic and model-based analysis in the context of chimeric antigen receptors (CAR) T-cell therapy
The aim of my thesis is to explore if the bulk of information derived from Kinetic studies may adequately contribute to establish the CAR T-cell therapy efficacy and safety profile, as it does for non-cell based medicinal products. The thesis addresses the main aspects that differentiate cellular-based products PK profile from biological and chemical drug PK profiles.
Classical PK parameters are not directly applicable to CART cells products, because the latter are replicating cell-based products. As direct consequence of their proliferate capacity, CAR-T cellular kinetics can be described by the following phases: distribution, expansion, contraction, and persistence. Consequently, the main issues that need to be addressed in the study of the PK profile of CAR T-cells are self-proliferation capabilities and long-term persistence. Peculiarities in CAR T-cells kinetics mainly impact on dose selection and on dose-exposure relationship, both of which are deeply discussed in my thesis. Finally, the thesis investigates the use of modelling as a potential tool to take into account the main variables that influence CAR T-cell kinetics.