BioModels

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https://www.ebi.ac.uk/biomodels/model/download/MODEL1909050002?filename=Ribba2018%20Model%202.xmlhttps://www.ebi.ac.uk/biomodels/model/download/MODEL1909050002?filename=Ribba2018%20Model%202.cpsprimary200OKJohannes MeyerNon-curatedordinary differential equation modelL2V4Immuno-oncologyhttps://www.ebi.ac.uk/biomodels/MODEL190905000229463551falseBioModelsModelsSBMLRibba2018 Mathematical Model of Tumor Uptake for Immunocytokine Based Cancer Immunotherapy2018MODEL1909050002Benjamin RibbaBenjamin Ribba, Christophe Boetsch, Tapan Nayak, Hans Peter Grimm, Jehad Charo, Stefan Evers, Christian Klein, Jean Tessier, Jean Eric Charoin, Alex Phipps, Pavel Pisa, Volker Teichgräber29463551, Purpose: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities.Experimental Design: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL2 receptor-positive cell populations (i.e., CD8+, CD4+, NK, and B cells), which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues.Results: We created a pharmacokinetic/pharmacodynamic mathematical model that incorporates the expansion of IL2R-positive target cells at multiple dose levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL2R-positive cells.Conclusions: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anticancer immunotherapy. Clin Cancer Res; 24(14); 3325-33. ©2018 AACRSee related commentary by Ruiz-Cerdá et al., p. 3236.. 14, 24. Pharmaceutical Sciences, Roche Pharmaceutical Research & Early Development, Roche Innovation Center, Basel, Switzerland. benjamin.ribba@roche.com.johannes.p.meyer@gmail.comEMBL-EBIPurpose: Optimal dosing is critical for immunocytokine-based cancer immunotherapy to maximize efficacy and minimize toxicity. Cergutuzumab amunaleukin (CEA-IL2v) is a novel CEA-targeted immunocytokine. We set out to develop a mathematical model to predict intratumoral CEA-IL2v concentrations following various systemic dosing intensities.Experimental Design: Sequential measurements of CEA-IL2v plasma concentrations in 74 patients with solid tumors were applied in a series of differential equations to devise a model that also incorporates the peripheral concentrations of IL2 receptor-positive cell populations (i.e., CD8+, CD4+, NK, and B cells), which affect tumor bioavailability of CEA-IL2v. Imaging data from a subset of 14 patients were subsequently utilized to additionally predict antibody uptake in tumor tissues.Results: We created a pharmacokinetic/pharmacodynamic mathematical model that incorporates the expansion of IL2R-positive target cells at multiple dose levels and different schedules of CEA-IL2v. Model-based prediction of drug levels correlated with the concentration of IL2R-positive cells in the peripheral blood of patients. The pharmacokinetic model was further refined and extended by adding a model of antibody uptake, which is based on drug dose and the biological properties of the tumor. In silico predictions of our model correlated with imaging data and demonstrated that a dose-dense schedule comprising escalating doses and shortened intervals of drug administration can improve intratumoral drug uptake and overcome consumption of CEA-IL2v by the expanding population of IL2R-positive cells.Conclusions: The model presented here allows simulation of individualized treatment plans for optimal dosing and scheduling of immunocytokines for anticancer immunotherapy. Clin Cancer Res; 24(14); 3325-33. ©2018 AACRSee related commentary by Ruiz-Cerdá et al., p. 3236.Prediction of the Optimal Dosing Regimen Using a Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy.Ribba Benjamin B, Boetsch Christophe C, Nayak Tapan T, Grimm Hans Peter HP, Charo Jehad J, Evers Stefan S, Klein Christian C, Tessier Jean J, Charoin Jean Eric JE, Phipps Alex A, Pisa Pavel P, Teichgräber Volker VfalseRibba2018 - Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy This is a model developed to predict concentrations of cergutuzumab amunaleukin (CEA-IL2v) after various systemic dosing intensities. 2019-09-052019-11-132019-09-05MODEL190905000229463551C14145910.1158/1078-0432.CCR-17-2953