Application of Mechanistic Modeling to Support Dose‐Relevant Decision Making for CAR‐T Cell Therapy in Oncology: A Systematic Scoping Review
- 1Centre for Pharmaceutical Medicine Research, School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London London UK
Abstract
CAR‐T therapy has improved outcomes in selected relapsed or refractory hematologic malignancies. However, rational dose‐relevant decision application remains challenging because the administered (nominal) cell dose does not reliably predict in vivo exposure, toxicity, or clinical response. These relationships are not adequately characterized by empirical dose escalation alone. Mechanistic modeling may offer a biologically interpretable way to connect preclinical evidence and patient‐level CAR‐T posology, but its application remains incompletely defined. We conducted a systematic scoping review using JBI methodology and PRISMA‐ScR guidance, searching MEDLINE, Embase, Scopus, and Google Scholar (2010–2025). Eligible studies reported original CK/PD, PK/PD, QSP, PBPK/PD, stochastic, or agent‐based models for dose‐relevant application or regimen optimization. Nineteen studies met the inclusion criteria (13 mechanistic and 6 semi‐mechanistic models) spanning hematologic and solid‐tumor settings. Although these studies evaluated aspects of CAR‐T pharmacology, none provided prospectively validated clinical dose‐selection evidence. Overall, CAR‐T expansion appeared to be more influenced by tumor burden, antigen engagement, product‐specific attributes, lymphodepletion, and host or tumor‐site factors than by nominal dose. Solid‐tumor models highlighted delivery route, trafficking, biodistribution, and microenvironment barriers. Emerging in vivo CAR‐T platforms shifted dose considerations toward vector or mRNA dose and repeat dosing. Mechanistic modeling appears useful for framing CAR‐T dose‐relevant and regimen questions, but the current evidence is best interpreted as a taxonomy of model applications rather than proof of prospective clinical dose selection utility. Consistent with ICH M15 principles, future clinical, and regulatory application will require defined context of use, stronger validation, uncertainty assessment, and biological integration.
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BibTeX
@article{odujinrin2026application,
title = {{Application of Mechanistic Modeling to Support Dose‐Relevant Decision Making for CAR‐T Cell Therapy in Oncology: A Systematic Scoping Review}},
author = {Dolapo Odujinrin and Graham McClelland},
journal = {Clinical and Translational Science},
year = {2026},
month = nov,
doi = {10.1111/cts.70756},
url = {https://doi.org/10.1111/cts.70756},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Application of Mechanistic Modeling to Support Dose‐Relevant Decision Making for CAR‐T Cell Therapy in Oncology: A Systematic Scoping Review
AU - Dolapo Odujinrin
AU - Graham McClelland
PY - 2026
DA - 2026/11/06
JO - Clinical and Translational Science
DO - 10.1111/cts.70756
UR - https://doi.org/10.1111/cts.70756
AB - CAR‐T therapy has improved outcomes in selected relapsed or refractory hematologic malignancies. However, rational dose‐relevant decision application remains challenging because the administered (nominal) cell dose does not reliably predict in vivo exposure, toxicity, or clinical response. These relationships are not adequately characterized by empirical dose escalation alone. Mechanistic modeling may offer a biologically interpretable way to connect preclinical evidence and patient‐level CAR‐T posology, but its application remains incompletely defined. We conducted a systematic scoping review using JBI methodology and PRISMA‐ScR guidance, searching MEDLINE, Embase, Scopus, and Google Scholar (2010–2025). Eligible studies reported original CK/PD, PK/PD, QSP, PBPK/PD, stochastic, or agent‐based models for dose‐relevant application or regimen optimization. Nineteen studies met the inclusion criteria (13 mechanistic and 6 semi‐mechanistic models) spanning hematologic and solid‐tumor settings. Although these studies evaluated aspects of CAR‐T pharmacology, none provided prospectively validated clinical dose‐selection evidence. Overall, CAR‐T expansion appeared to be more influenced by tumor burden, antigen engagement, product‐specific attributes, lymphodepletion, and host or tumor‐site factors than by nominal dose. Solid‐tumor models highlighted delivery route, trafficking, biodistribution, and microenvironment barriers. Emerging in vivo CAR‐T platforms shifted dose considerations toward vector or mRNA dose and repeat dosing. Mechanistic modeling appears useful for framing CAR‐T dose‐relevant and regimen questions, but the current evidence is best interpreted as a taxonomy of model applications rather than proof of prospective clinical dose selection utility. Consistent with ICH M15 principles, future clinical, and regulatory application will require defined context of use, stronger validation, uncertainty assessment, and biological integration.
SN - 1752-8054
SN - 1752-8062
ER -