Speaker
Description
Antigen Receptor (CAR) T-cell therapy has transformed cancer immunotherapy by genetically engineering T-cells to target tumor antigens. Acute myeloid leukemia (AML) presents unique challenges due to resistance mechanisms, especially in patients with TP53 loss mutations.
The complex dynamics of CAR T-cell expansion remain poorly understood. The field lacks validated quantitative frameworks to systematically evaluate different CAR T-cell target constructs, such as CD33, CD123, and CD371, against resistant AML variants. We address this gap by combining mathematical modeling with in vitro assay data and Bayesian inference. We select, train, and validate a two-compartment deterministic mathematical model that describes the nonlinear dynamics of target AML and CAR T cells, accounting for expansion, killing, and exhaustion. Using Bayesian inference, we train and select the best-performing functional form for CAR T expansion, and then validate it on unseen data. Our framework selects a model that accounts for handling time and T-cell self-interference. Thus, expansion is a complex and dynamic process in which the handling time of target cells and T-cell crowding negatively affect T-cell expansion. Analysis of posterior parameter distributions reveals target-antigen-specific responses against TP53-deficient AML. For instance, CD33-targeting CARs have reduced attack rates against TP53-deficient cells, while CD123- and CD371-targeting CARs show moderately increased attack rates; however, the former exhibit higher death rates, and the latter have increased handling times, impeding efficacy. This target-dependent form of resistance challenges the assumption of uniform performance and reveals a unifying nonlinear expansion model for integrated, yet antigen-specific, experimental and theoretical predictions of efficacy.
