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.

13.06.2024

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

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.

19/06/23