Speaker
Description
Malignant gliomas (MGs) remain highly resistant to conventional treatments. We propose an ordinary differential equation model to investigate the potential synergistic dynamics between standard therapy (radiotherapy (RT) and temozolomide (TMZ)) \cite{Stupp} and chimeric antigen receptor (CAR) T-cell therapy \cite{Brown}. While both TMZ and RT can be lymphotoxic, TMZ may also enhance CAR T efficacy by upregulating tumor antigens and inducing lymphodepletion, and RT can promote T-cell infiltration.
Our model extends and combines our previous works \cite{Sinelshchikov,Perales}, consisting of a nine-dimensional dynamical system describing MG subpopulations and treatment dynamics and incorporating impulsive inputs to simulate clinical administration. Mathematical analysis reveals parameter regimes under which constant treatment administration achieves tumor eradication.
To bridge theory and clinical application, the model was validated using published trial data \cite{Stupp, Brown, Laigle}. We generated cohorts of virtual patients through random sampling within biologically and clinically relevant ranges to conduct in silico trials. Numerical simulations evaluate various treatment combinations to identify optimal protocols and parameter-derived biomarkers at the population level. Our results provide new theoretical insights into treatment scheduling and offer a mechanistic tool to optimize and personalize MG therapy.
Bibliography
@article{Brown,
title = {Regression of {Glioblastoma} after {Chimeric} {Antigen} {Receptor} {T}-{Cell} {Therapy}},
volume = {375},
issn = {0028-4793, 1533-4406},
url = {http://www.nejm.org},
doi = {10.1056/NEJMoa1610497},
language = {en},
number = {26},
journal = {New England Journal of Medicine},
author = {Brown, Christine E. and Alizadeh, Darya and Starr, Renate and Weng, Lihong and Wagner, Jamie R. and Naranjo, Araceli and Ostberg, Julie R. and Blanchard, M. Suzette and Kilpatrick, Julie and Simpson, Jennifer and Kurien, Anita and Priceman, Saul J. and Wang, Xiuli and Harshbarger, Todd L. and D'Apuzzo, Massimo and Ressler, Julie A. and Jensen, Michael C. and Barish, Michael E. and Chen, Mike and Portnow, Jana and Forman, Stephen J. and Badie, Behnam},
month = dec,
year = {2016},
pages = {2561--2569},
}
@article{Stupp,
title = {Radiotherapy plus {Concomitant} and {Adjuvant} {Temozolomide} for {Glioblastoma}},
volume = {352},
issn = {0028-4793, 1533-4406},
url = {http://www.nejm.org},
doi = {10.1056/NEJMoa043330},
language = {en},
number = {10},
journal = {New England Journal of Medicine},
author = {Stupp, Roger and Mason, Warren P. and Van Den Bent, Martin J. and Weller, Michael and Fisher, Barbara and Taphoorn, Martin J. B. and Belanger, Karl and Brandes, Alba A. and Marosi, Christine and Bogdahn, Ulrich and Curschmann, J{\"u}rgen and Janzer, Robert C. and Ludwin, Samuel K. and Gorlia, Thierry and Allgeier, Anouk and Lacombe, Denis and Cairncross, J. Gregory and Eisenhauer, Elizabeth and Mirimanoff, Ren{\'e} O.},
month = mar,
year = {2005},
pages = {987--996},
}
@article{Sinelshchikov,
title = {A mathematical model of {CAR}-{T} cell therapy in combination with chemotherapy for malignant gliomas},
volume = {35},
issn = {1054-1500, 1089-7682},
url = {https://pubs.aip.org},
doi = {10.1063/5.0260252},
number = {6},
journal = {Chaos: An Interdisciplinary Journal of Nonlinear Science},
author = {Sinelshchikov, Dmitry and Belmonte-Beitia, Juan and Italia, Matteo},
month = jun,
year = {2025},
pages = {063104},
}
@misc{Perales,
title = {Optimizing chemoradiotherapy for malignant gliomas: a validated mathematical approach},
publisher = {arXiv},
url = {https://arxiv.org},
doi = {10.48550/ARXIV.2504.17481},
author = {Perales-Pat{\'o}n, Miguel and Italia, Matteo and Castell{\'o}-Pons, Mar{\'i}a and G{\'o}mez-Soria, Irene and Belmonte-Beitia, Juan and S{\'a}nchez-G{\'o}mez, Pilar and P{\'e}rez-Garc{\'i}a, V{\'i}ctor M.},
year = {2025},
}
@article{Laigle,
title = {Up-front temozolomide in elderly patients with glioblastoma},
volume = {99},
issn = {0167-594X, 1573-7373},
url = {http://link.springer.com},
doi = {10.1007/s11060-009-0110-3},
language = {en},
number = {1},
journal = {Journal of Neuro-Oncology},
author = {Laigle-Donadey, Florence and Figarella-Branger, Dominique and Chinot, Olivier and Taillandier, Luc and Cartalat-Carel, St{\'e}phanie and Honnorat, J{\'e}r{\^o}me and Kaloshi, Gentian and Delattre, Jean-Yves and Sanson, Marc},
month = aug,
year = {2010},
pages = {89--94},}
