With the FDA approval of Kymriah® and Yescarta®, Chimeric Antigen Receptor (CAR)-T cell therapy has achieved tremendous success, especially in the treatment of B-cell hematological malignancies. Previous studies have shown that in vivo CAR-T cellular kinetics typically involves four distinct phases of distribution, expansion, contraction, and persistence. However, the translational pharmacokinetic (PK) and pharmacodynamic (PD) aspects as well as the dose-exposure-response relationships for CAR-Ts remain poorly understood. This presentation details PK/PD approaches to establish a rationale for the FIH starting dose as well as for efficacious or threshold dose projections for CAR-T cell therapies. It is also imperative to execute quantitative assessments from dose escalation studies for CAR-Ts already in the clinic including PK/PD correlations. Finally, multiscale semi-mechanistic PK/PD modeling approaches that accounts for the engagement of CAR-T with tumor to drive response (efficacy and toxicity) can be utilized for human starting and efficacious dose projections, once thoroughly validated.
To discuss PK/PD considerations and approaches utilized to establish a starting dose rationale as well as for efficacious dose projections for CAR-T cell therapies.
To better understand PK/PD correlations and relationships from the dose escalation studies of CAR-Ts in clinics.
To demonstrate how we can leverage semi-mechanistic PK/PD modeling approaches for human starting and efficacious dose projections, once validated.