Prediction of the Optimal Dosing Regimen Using a Mathematical Model of Tumor Uptake for Immunocytokine-Based Cancer Immunotherapy

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Benjamin RibbaVolker Teichgräber

Abstract

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 upta...Continue Reading

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Citations

Aug 15, 2018·Clinical Pharmacology and Therapeutics·Imke H BartelinkGeraldine Gebhart
Mar 1, 2019·Clinical Pharmacokinetics·Maddalena CentanniJ G Coen van Hasselt
Sep 13, 2019·The AAPS Journal·Pascal SchulthessPiet H van der Graaf
Oct 28, 2019·Clinical Pharmacokinetics·Belén P SolansIñaki F Trocóniz
Jun 20, 2020·Clinical Pharmacology and Therapeutics·Sebastien Benzekry
Nov 7, 2019·Computational and Mathematical Methods in Medicine·Pranav Unni, Padmanabhan Seshaiyer
Sep 10, 2020·Frontiers in Immunology·John A HangaskyDaniel V Santi
Mar 28, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Leire Ruiz-CerdáIñaki F Trocóniz
Jan 26, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Guolan LuEben L Rosenthal
Sep 4, 2020·Clinical and Translational Science·Peter N MorcosChi-Chung Li
Jun 2, 2021·Journal for Immunotherapy of Cancer·Jeroen H A CreemersJohannes Textor
Aug 11, 2021·Pharmaceutics·Aymara Sancho-AraizIñaki F Trocóniz

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