Combining standard chemoradiotherapy with CAR-T cell therapy in malignant gliomas: Insights from an impulsive mathematical framework and virtual trials
Abstract
The extreme therapeutic resistance of malignant gliomas motivates the development of multimodal treatment strategies. We present a mechanistic mathematical framework to investigate the coupled dynamics of radiotherapy, temozolomide, and chimeric antigen receptor (CAR) T-cell therapy. The model is formulated as a nine-dimensional impulsive dynamical system that captures proliferative-quiescent tumor states, treatment-specific resistance, tissue damage, TMZ pharmacokinetics, and the lymphotoxic interferences exerted by conventional regimens on engineered T cells. Mathematical analysis establishes the existence of biologically meaningful solutions, maps invariant structures, and identifies threshold conditions under which sustained therapy locally stabilizes the tumor-free equilibrium. After study-matched benchmarking against clinical trials, including the standard Stupp protocol, we deploy heterogeneous virtual patient cohorts to evaluate five combined CAR-T--Stupp sequences. At the population level, the immunotherapeutic adjunct yields a consistent but modest survival extension, increasing median overall survival by $0.8−−0.9$ months with minimal sensitivity to temporal ordering or scheduling perturbations. Crucially, these population-level medians mask profound individual heterogeneity: under combined protocols, 19%--22% of virtual patients extend survival by more than $60$ days, and ∼ 3% gain over a year. A low intrinsic tumor proliferation rate r1 emerges as the primary determinant of response, bolstered by robust T-cell expansion and attenuated microenvironmental suppression. These findings suggest that the clinical promise of multimodal integration depends on identifying responsive tumor phenotypes for personalized treatments rather than searching for a single universally optimal timeline.
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BibTeX
@misc{sinelshchikov2026combining,
title = {{Combining standard chemoradiotherapy with CAR-T cell therapy in malignant gliomas: Insights from an impulsive mathematical framework and virtual trials}},
author = {Dmitry Sinelshchikov and Nikols Amaru Mora Millán and Miguel Perales-Patón and Juan Belmonte-Beitia and Matteo Italia},
howpublished = {arXiv},
year = {2026},
month = sep,
doi = {10.48550/arxiv.2609.39191},
eprint = {2609.39191},
archivePrefix = {arXiv},
url = {https://arxiv.org/abs/2609.39191},
}
RIS
TY - UNPB
TI - Combining standard chemoradiotherapy with CAR-T cell therapy in malignant gliomas: Insights from an impulsive mathematical framework and virtual trials
AU - Dmitry Sinelshchikov
AU - Nikols Amaru Mora Millán
AU - Miguel Perales-Patón
AU - Juan Belmonte-Beitia
AU - Matteo Italia
PY - 2026
DA - 2026/09/30
PB - arXiv
DO - 10.48550/arxiv.2609.39191
UR - https://arxiv.org/abs/2609.39191
AB - The extreme therapeutic resistance of malignant gliomas motivates the development of multimodal treatment strategies. We present a mechanistic mathematical framework to investigate the coupled dynamics of radiotherapy, temozolomide, and chimeric antigen receptor (CAR) T-cell therapy. The model is formulated as a nine-dimensional impulsive dynamical system that captures proliferative-quiescent tumor states, treatment-specific resistance, tissue damage, TMZ pharmacokinetics, and the lymphotoxic interferences exerted by conventional regimens on engineered T cells. Mathematical analysis establishes the existence of biologically meaningful solutions, maps invariant structures, and identifies threshold conditions under which sustained therapy locally stabilizes the tumor-free equilibrium. After study-matched benchmarking against clinical trials, including the standard Stupp protocol, we deploy heterogeneous virtual patient cohorts to evaluate five combined CAR-T--Stupp sequences. At the population level, the immunotherapeutic adjunct yields a consistent but modest survival extension, increasing median overall survival by $0.8−−0.9$ months with minimal sensitivity to temporal ordering or scheduling perturbations. Crucially, these population-level medians mask profound individual heterogeneity: under combined protocols, 19%--22% of virtual patients extend survival by more than $60$ days, and ∼ 3% gain over a year. A low intrinsic tumor proliferation rate r_1 emerges as the primary determinant of response, bolstered by robust T-cell expansion and attenuated microenvironmental suppression. These findings suggest that the clinical promise of multimodal integration depends on identifying responsive tumor phenotypes for personalized treatments rather than searching for a single universally optimal timeline.
ER -