Optimizing CAR-T cell exposure

• Therapeutic area: Oncology
• Phase I — III
• Impact: Informing

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.

Selection of computational CAR-T cell models that can be used in a model-informed drug development strategy, grouped by the applied modeling approach.

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