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Mathematical Modeling of IL-12 Immunotherapy of Solid Cancers

Mathematical Modeling of IL-12 Immunotherapy of Solid Cancers. +. Secretion. +. Proliferation. -. Removal. -. Control. +. IL-12. IL-12. Treg. +. +. +. IL-10. Treg. -. Th1 Shift. +. +. +. -. IL-10. +. IL-2. +. Regev Zaidenstein 1 , David Corcos 1. +. +. +. +.

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Mathematical Modeling of IL-12 Immunotherapy of Solid Cancers

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  1. Mathematical Modeling of IL-12 Immunotherapy of Solid Cancers + Secretion + Proliferation - Removal - Control + IL-12 IL-12 Treg + + + IL-10 Treg - Th1 Shift + + + - IL-10 + IL-2 + • RegevZaidenstein1, David Corcos1 + + + + Results:First we constructed a qualitative description of the IL-12 induced anti-tumor immune response, based on phenomenological observations (Figure 2). we further simplified the model (figure 3) excluding non essential components. Once a qualitative model was established we formulated the equations (figure 4) . + + IFN-γ IL-2 + + IFN-γ + - DC Under the supervision of Moran Elishmereni2, Prof. ZviaAgur2 + + Objectives:The aim of our work is to construct a mathematical model of IL-12’s immunotherapeutic effects. Such model shall reproduce clinical data and predict patients’ responses to different administration protocols. + + CTL 1Department of Biomedical Engineering, Engineering Faculty Tel Aviv university + NK + CTL - + NK + + - - - • 2The Institute for Medical BioMathematics (IMBM) + + Tumor - - Tumor - - Introductions:Immunotherapy is the artificial modulation of natural immune responses aimed at treating a disease, and it ranks among the most promising treatment strategies against cancer. Experimental data from murine models showed that interleukin (IL)-12, a cytokine produced by macrophages and dendritic cells, can lead to complete tumor eradication. However, to date clinical trials have failed to induce significant responses to IL-12 based treatments. Hence, a mathematical model describing the pharmacokinetics and pharmacodynamics of the drug investigated can provide the basis for the design of effective immunotherapeutic regimens, by means of optimization techniques. The aim of our current work is to provide such a model, based on both clinical and experimental data. 3.Simplified Model 4.Equations 1.Experimental Data A. Tumordynamics B. CTL dynamics 2.Comprehensive Model Materials and methods: Our model employed a set of ODEs. The system includes equations reproducing proliferation and death rate of tumor cells and lymphocytes, and secretion and clearance rates of the cytokines. Lymphocytes populations are modeled by logistic functions. As for the cytokines, they are usually secreted at a rate directly proportional to the number of secreting cells, until they reach saturation. In order to calibrate the parameters, experimental data (figure 1) is usually divided into a training set and a test set. The model shall be implemented in silico in order to reproduce clinical results. Conclusions and Future Work:A mathematical model of IL-12 Immunotherapy For Solid Cancers was constructed. Optimization of the established model shall be carried out to find an optimal course of treatment, utilizing a cost function that takes into account duration, tumor reduction, and toxicity. C. Cytokinesdynamics A. Portielje J.E.A. (2003). B. Dias S (1998). C. Lu J (2002)

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