Speaker
Description
Neuroblastoma is the most common extracranial solid tumor in children, where high-risk cases often face poor prognosis. We propose an ordinary differential equation model to investigate optimal combined dynamics between chemotherapy (Cyclophosphamide) \cite{Garaventa} and oncolytic virotherapy (Celyvir, mesenchymal stem cells carrying the adenovirus ICOVIR-5)\cite{Melen}, combining our previous works on chemotherapy \cite{Italia} and virotherapy \cite{Otero}.
The mechanistic model incorporates interactions between tumor, immune system, virus, and drug. Calibrated using published data, we perform mathematical analysis to identify threshold values for treatment administrations required to eliminate the tumor. Through sensitivity analysis, we determine key parameters driving treatment outcomes, serving as potential biomarkers.
We formulated an optimal control problem with a nonlinear objective functional aimed at minimizing tumor burden and treatment toxicity \cite{Pontrjagin}. We show that periodic bang-bang control regimes optimize the delivery of Celyvir, while singular control can characterizes the chemotherapy regimen. By conducting in silico trials on virtual patient cohorts, we assessed the effects of patient heterogeneities on optimal solutions. Our results demonstrate that personalized scheduling, informed by patient-specific data, can significantly optimize combined treatment outcomes, providing a mechanistic-based foundation for clinical decision support systems.
Bibliography
@article{Garaventa,
title = {Randomized {Trial} of {Two} {Induction} {Therapy} {Regimens} for {High}-{Risk} {Neuroblastoma}: {HR}-{NBL1}.5 {International} {Society} of {Pediatric} {Oncology} {European} {Neuroblastoma} {Group} {Study}},
volume = {39},
issn = {0732-183X, 1527-7755},
shorttitle = {Randomized {Trial} of {Two} {Induction} {Therapy} {Regimens} for {High}-{Risk} {Neuroblastoma}},
url = {https://ascopubs.org/doi/10.1200/JCO.20.03144},
doi = {10.1200/JCO.20.03144},
number = {23},
urldate = {2026-03-11},
journal = {Journal of Clinical Oncology},
author = {Garaventa, Alberto and Poetschger, Ulrike and Valteau-Couanet, Dominique and Luksch, Roberto and Castel, Victoria and Elliott, Martin and Ash, Shifra and Chan, Godfrey C. F. and Laureys, Genevi{`e}ve and Beck-Popovic, Maja and Vettenranta, Kim and Balwierz, Walentyna and Schroeder, Henrik and Owens, Cormac and Cesen, Maja and Papadakis, Vassilios and Trahair, Toby and Schleiermacher, Gudrun and Ambros, Peter and Sorrentino, Stefania and Pearson, Andrew D. J. and Ladenstein, Ruth Lydia},
month = aug,
year = {2021},
pages = {2552--2563},
}
@article{Melen,
title = {Influence of carrier cells on the clinical outcome of children with neuroblastoma treated with high dose of oncolytic adenovirus delivered in mesenchymal stem cells},
volume = {371},
issn = {03043835},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0304383515007260},
doi = {10.1016/j.canlet.2015.11.036},
language = {en},
number = {2},
urldate = {2026-03-11},
journal = {Cancer Letters},
author = {Mel{\'e}n, Gustavo J. and Franco-Luz{\'o}n, Lidia and Ruano, David and Gonz{\'a}lez-Murillo, {\'A}frica and Alfranca, Arantzazu and Casco, Fernando and Lassaletta, {\'A}lvaro and Alonso, Mercedes and Madero, Lu{\'i}s and Alemany, Ram{\'o}n and Garc{\'i}a-Castro, Javier and Ram{\'i}rez, Manuel},
month = feb,
year = {2016},
pages = {161--170},
}
@article{Italia,
title = {Mathematical {Model} of {Clonal} {Evolution} {Proposes} a {Personalised} {Multi}-{Modal} {Therapy} for {High}-{Risk} {Neuroblastoma}},
volume = {15},
issn = {2072-6694},
url = {https://www.mdpi.com/2072-6694/15/7/1986},
doi = {10.3390/cancers15071986},
number = {7},
urldate = {2026-03-11},
journal = {Cancers},
author = {Italia, Matteo and Wertheim, Kenneth Y. and Taschner-Mandl, Sabine and Walker, Dawn and Dercole, Fabio},
month = mar,
year = {2023},
pages = {1986},
}
@article{Otero,
title = {On the dynamics and optimal control of a mathematical model of neuroblastoma and its treatment: {Insights} from a mathematical model},
volume = {34},
issn = {0218-2025, 1793-6314},
shorttitle = {On the dynamics and optimal control of a mathematical model of neuroblastoma and its treatment},
url = {https://www.worldscientific.com/doi/10.1142/S0218202524500210},
doi = {10.1142/S0218202524500210},
number = {07},
urldate = {2026-03-11},
journal = {Mathematical Models and Methods in Applied Sciences},
author = {Garc{\'i}a Otero, Jos{\'e} and Bodzioch, Mariusz and Belmonte-Beitia, Juan},
month = jun,
year = {2024},
pages = {1235--1278},
}
@book{Pontrjagin,
address = {Boca Raton},
edition = {4th ed},
series = {Classics of {Soviet} {Mathematics}},
title = {Mathematical {Theory} of {Optimal} {Processes}},
isbn = {9782881240775 9781351433075},
language = {eng},
publisher = {Routledge},
author = {Pontrjagin, Lev S.},
year = {2018},
}
