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Quantifying target antigen-dependent CAR T-cell performance against AML
Saumil Shah1, Jan Mueller2,3, Emanuel Vogel3
1Department of Theoretical Biology, Max Planck Institute for Evolutionary Biology, Plön, Germany.
Cancer Cell International
|July 29, 2026
Summary
Mathematical modeling reveals that CAR T-cell expansion dynamics are complex, with target-cell handling time and crowding negatively impacting efficacy against Acute Myeloid Leukemia (AML), especially in TP53-mutated cancers.
Area of Science:
- Immunotherapy
- Computational Biology
- Hematologic Oncology
Background:
- Chimeric Antigen Receptor (CAR) T-cell therapy is a promising cancer immunotherapy.
- Acute Myeloid Leukemia (AML), particularly with TP53 loss mutations, presents significant treatment resistance challenges.
- Understanding CAR T-cell expansion dynamics is crucial for optimizing therapy but remains poorly understood.
Purpose of the Study:
- To develop and validate a quantitative framework for evaluating different CAR T-cell targets against resistant AML.
- To elucidate the complex dynamics of CAR T-cell expansion and identify resistance mechanisms.
- To enable antigen-specific preclinical predictions of CAR T-cell therapy efficacy.
Main Methods:
- Combined mathematical modeling with in vitro assay data and Bayesian inference.
- Developed and validated a two-compartment deterministic model for CAR T-cell and AML dynamics.
- Employed Bayesian inference to train and select a nonlinear CAR T-cell expansion model accounting for handling time and self-interference.
Main Results:
- Identified a unifying nonlinear CAR T-cell expansion model influenced by handling time and T-cell crowding.
- Demonstrated target-antigen-specific responses against TP53-deficient AML.
- CD33-targeting CARs showed reduced attack rates, while CD123- and CD371-targeting CARs exhibited altered attack and death rates, impacting overall efficacy.
Conclusions:
- CAR T-cell expansion is a dynamic process significantly affected by target-cell handling and T-cell density.
- Resistance mechanisms in TP53-deficient AML are target-dependent, challenging uniform efficacy assumptions.
- The developed framework allows for integrated, antigen-specific preclinical predictions of CAR T-cell therapy in AML.
