Optimizing CAR-T cell exposure

About the case

Therapeutic area: Oncology
Phase I — III
Impact: Informing

Principal question

In absence of clear dose-exposure relationships, are there other means to optimize CAR-T cell exposure?

• The main challenge was that although positive exposure-response relationships have been identified for CAR-T cell therapy, traditional dose-exposure relationships do not apply.

• The main impact was the identification of potential MIDD applications for the development of CAR-T cell therapies.

• Pharmetheus identified i) actionable variables which can be modified to optimize exposure; ii) suitable mathematical models to support such optimization processes.

• The method included a review of relevant literature and published computational CAR-T cell models.

Drug discovery

• Optimization of the CAR affinity

• Selection and optimization of the CAR hinge/spacer domain

• Selection of the CAR co-stimulatory domain(s)

• Selection and optimization of CAR element combinations

Drug development

• Stimulation of cells during the ex vivo expansion

• Optimization of the duration of the ex vivo expansion

• Cytokines in the ex vivo expansion medium and their concentrations

Clinical practice

• Selection of patients who might benefit from bridging therapy and optimization of bridging treatment

• Optimization of preconditioning lymphodepleting chemotherapy

• Combination of CAR-T cells with other treatments

Linked publication

Model-informed drug development of autologous CAR-T cell therapy: Strategies to optimize CAR-T cell exposure leveraging cell kinetic/dynamic modeling.

CPT Pharmacometrics Syst Pharmacol. 2023 Nov;12(11):1577-1590

Mc Laughlin AM, Milligan PA, Yee C, Bergstrand M.