Optimizing CAR-T cell exposure

CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Clear dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. Dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR-T cells. Model-informed drug development approaches can, through enabling studies and program design choices, be an important contributor to alternative approaches beyond dose titration to optimize CAR-T cell therapy.


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.
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