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Bench-to-bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic-pharmacodynamic model: A case study with anti-BCMA CAR-T.
- Source :
-
CPT: pharmacometrics & systems pharmacology [CPT Pharmacometrics Syst Pharmacol] 2021 Apr; Vol. 10 (4), pp. 362-376. Date of Electronic Publication: 2021 Mar 24. - Publication Year :
- 2021
-
Abstract
- Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose-exposure-response relationship of CAR-T cells in patients is poorly understood. Moreover, the key drug-specific and system-specific determinants leading to favorable clinical outcomes are also unknown. Here we have developed a multiscale mechanistic pharmacokinetic (PK)-pharmacodynamic (PD) model for anti-B-cell maturation antigen (BCMA) CAR-T cell therapy (bb2121) to characterize (i) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying effector to target cell ratios, (ii) preclinical in vivo tumor growth inhibition and blood CAR-T cell expansion in xenograft mice, and (iii) clinical PK and PD biomarkers in patients with multiple myeloma. Our translational PK-PD relationship was able to effectively describe the commonly observed multiphasic CAR-T cell PK profile in the clinic, consisting of the rapid distribution, expansion, contraction, and persistent phases, and accounted for the categorical individual responses in multiple myeloma to effectively calculate progression-free survival rates. Preclinical and clinical data analysis revealed comparable parameter estimates pertaining to CAR-T cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels toward overall extent of exposure after CAR-T cell infusion. Virtual patient simulations also suggested a very steep dose-exposure-response relationship with CAR-T cell therapy and indicated the presence of a "threshold" dose, beyond which a flat dose-response curve could be observed. Our simulations were concordant with multiple clinical observations discussed in this article. Moving forward, this framework could be leveraged a priori to explore multiple infusions and support the preclinical/clinical development of future CAR-T cell therapies.<br /> (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Animals
Antineoplastic Agents, Immunological administration & dosage
Biomarkers, Pharmacological analysis
Cell Line, Tumor drug effects
Computer Simulation
Dose-Response Relationship, Drug
Humans
Immunotherapy, Adoptive methods
Infusions, Intravenous
Mice
Mice, Inbred NOD
Models, Theoretical
Pharmacokinetics
Progression-Free Survival
Receptors, Chimeric Antigen administration & dosage
Receptors, Chimeric Antigen immunology
Receptors, Chimeric Antigen metabolism
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes transplantation
Xenograft Model Antitumor Assays methods
Antineoplastic Agents, Immunological therapeutic use
B-Cell Maturation Antigen antagonists & inhibitors
Multiple Myeloma therapy
Receptors, Chimeric Antigen therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 2163-8306
- Volume :
- 10
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- CPT: pharmacometrics & systems pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33565700
- Full Text :
- https://doi.org/10.1002/psp4.12598