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

Autor: Mc Laughlin AM; Pharmetheus AB, Uppsala, Sweden., Milligan PA; Pharmetheus AB, Uppsala, Sweden., Yee C; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Bergstrand M; Pharmetheus AB, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2023 Nov; Vol. 12 (11), pp. 1577-1590. Date of Electronic Publication: 2023 Jul 28.
DOI: 10.1002/psp4.13011
Abstrakt: Autologous Chimeric antigen receptor (CAR-T) cell therapy has been highly successful in the treatment of aggressive hematological malignancies and is also being evaluated for the treatment of solid tumors as well as other therapeutic areas. A challenge, however, is that up to 60% of patients do not sustain a long-term response. Low CAR-T cell exposure has been suggested as an underlying factor for a poor prognosis. CAR-T cell therapy is a novel therapeutic modality with unique kinetic and dynamic properties. Importantly, "clear" dose-exposure relationships do not seem to exist for any of the currently approved CAR-T cell products. In other words, dose increases have not led to a commensurate increase in the measurable in vivo frequency of transferred CAR-T cells. Therefore, alternative approaches beyond dose titration are needed to optimize CAR-T cell exposure. In this paper, we provide examples of actionable variables - design elements in CAR-T cell discovery, development, and clinical practice, which can be modified to optimize autologous CAR-T cell exposure. Most of these actionable variables can be assessed throughout the various stages of discovery and development as part of a well-informed research and development program. Model-informed drug development approaches can enable such study and program design choices from discovery through to clinical practice and can be an important contributor to cell therapy effectiveness and efficiency.
(© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje