Sa.65. Biosimulations Predict Optimal Oral Insulin/Anti-CD3 and Oral Insulin/Exendin-4 Combination Treatment Regimens for the Reversal of Diabetes in the Non-Obese Diabetic (NOD) Mouse

Zheng, Yanan; Bresson, Damien; Fradkin, Matthew; Chan, Jason R.; Herrath, Matthias von; Whiting, Chan C.

doi:10.1016/j.clim.2008.03.286

Cited by 4 publications

(6 citation statements)

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“…Mathematical modeling using systems of ordinary differential equations (ODEs) can improve the design and administration of cancer treatments, especially when experimental data are incorporated ( [8], [9], [10], [11], [12], [13]). In silico screening of parameter regions that seem most promising for optimal timing and dosage of therapy can be suggested using calibrated mathematical models and clinical trials can focus on those regions ( [13], [14], [15], [16], [17]). For instance, a quantitative systems pharmacology model in [8] was developed to reproduce experimental data of CT26 tumor size dynamics upon administration of RT and an anti-PD-L1 agent in ( [18], [19]).…”

Section: Resultsmentioning

confidence: 99%

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An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

Wang

et al. 2019

Preprint

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Section: Resultsmentioning

confidence: 99%

“…Interleukin-12 (IL-12) is produced by APCs at a rate of c 5 ·APC 3 and decays naturally at a rate of k d8 ·IL. The extra IL-12 expression obtained through the combined therapy is approximated using a discrete equation (16).…”

Section: E1mentioning

confidence: 99%

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

Wang

et al. 2019

Preprint

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“…We use the difference Eqs. (16) and (17) to reflect the abrupt changes in the concentrations of IL-12 and OXP caused by the therapies, respectively. The sudden change in the volume of MHC class I negative tumor cells due to tumor re-challenge is described by the difference Eq.…”

Section: E1mentioning

confidence: 99%

“…Mathematical modeling using systems of ordinary differential equations (ODEs) can improve the design and administration of cancer treatments, especially when experimental data are incorporated [8][9][10][11][12][13]. In silico screening of parameter regions that seem most promising for optimal timing and dosage of therapy can be suggested using calibrated mathematical models and clinical trials can focus on those regions [13][14][15][16][17]. For instance, a quantitative systems pharmacology model [8] was developed to reproduce experimental data of CT26 tumor dynamics upon administration of radiation therapy and an anti-PD-L1 agent in [18] and [19].…”

Section: Introductionmentioning

confidence: 99%

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

Wang

et al. 2020

BMC Cancer

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Background: Combining anti-cancer therapies with orthogonal modes of action, such as direct cytotoxicity and immunostimulatory, hold promise for expanding clinical benefit to patients with metastatic disease. For instance, a chemotherapy agent Oxaliplatin (OXP) in combination with Interleukin-12 (IL-12) can eliminate pre-existing liver metastatic colorectal cancer and protect from relapse in a murine model. However, the underlying dynamics associated with the targeted biology and the combinatorial space consisting of possible dosage and timing of each therapy present challenges for optimizing treatment regimens. To address some of these challenges, we developed a predictive simulation platform for optimizing dose and timing of the combination therapy involving Mifepristone-induced IL-12 and chemotherapy agent OXP. Methods: A multi-scale mathematical model comprised of impulsive ordinary differential equations was developed to describe the interaction between the immune system and tumor cells in response to the combined IL-12 and OXP therapy. An ensemble of model parameters were calibrated to published experimental data using a genetic algorithm and used to represent three different phenotypes: responders, partial-responders, and non-responders. Results: The multi-scale model captures tumor growth patterns of the three phenotypic responses observed in mice in response to the combination therapy against a tumor re-challenge and was used to explore the impacts of changing the dose and timing of the mixed immune-chemotherapy on tumor growth subjected to a tumor re-challenge in mice. An increased ratio of CD8+ T effectors to regulatory T cells during and after treatment was key to improve tumor control in the responder cohort. Sensitivity analysis indicates that combined OXP and IL-12 therapy worked more efficiently in responders by increased priming of T cells, enhanced CD8+ T cell-mediated killing, and functional inhibition of regulatory T cells. In a virtual cohort that mimics non-responders and partial-responders, simulations show that an increased dose of OXP alone would improve the response. In addition, enhanced IL-12 expression alone or an increased number of treatment cycles of the mixed immune-chemotherapy can barely improve tumor control for non-responders and partial responders. Conclusions: Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dose and timing in combined cancer treatment strategies.

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“…Mathematical modeling and simulations can be used to screen in silico parameter regions that seem most promising for optimal timing and dosage of therapy and clinical trials can be focused on those regions [ 30 - 32 ]. In [ 33 ], the authors explore how the timing of oral insulin delivery and immunomodulatory drugs can be optimized for maximum effect. Moreover, an in silico approach can suggest targeted experiments and then minimize the number of needed experiments [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

CD8 + T cell response to adenovirus vaccination and subsequent suppression of tumor growth: modeling, simulation and analysis

2015

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BackgroundUsing immune checkpoint modulators in the clinic to increase the number and activity of cytotoxic T lymphocytes that recognize tumor antigens can prolong survival for metastatic melanoma. Yet, only a fraction of the patient population receives clinical benefit. In short, these clinical trials demonstrate proof-of-principle but optimizing the specific therapeutic strategies remains a challenge. In many fields, CAD (computer-aided design) is a tool used to optimize integrated system behavior using a mechanistic model that is based upon knowledge of constitutive elements. The objective of this study was to develop a predictive simulation platform for optimizing anti-tumor immunity using different treatment strategies.MethodsTo better understand the therapeutic role that cytotoxic CD8 + T cells can play in controlling tumor growth, we developed a multi-scale mechanistic model of the biology using impulsive differential equations and calibrated it to a self-consistent data set.ResultsThe multi-scale model captures the activation and differentiation of naïve CD8 + T cells into effector cytotoxic T cells in the lymph node following adenovirus-mediated vaccination against a tumor antigen, the trafficking of the resulting cytotoxic T cells into blood and tumor microenvironment, the production of cytokines within the tumor microenvironment, and the interactions between tumor cells, T cells and cytokines that control tumor growth. The calibrated model captures the modest suppression of tumor cell growth observed in the B16F10 model, a transplantable mouse model for metastatic melanoma, and was used to explore the impact of multiple vaccinations on controlling tumor growth.ConclusionsUsing the calibrated mechanistic model, we found that the cytotoxic CD8 + T cell response was prolonged by multiple adenovirus vaccinations. However, the strength of the immune response cannot be improved enough by multiple adenovirus vaccinations to reduce tumor burden if the cytotoxic activity or local proliferation of cytotoxic T cells in response to tumor antigens is not greatly enhanced. Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dosage and timing in cancer treatment.

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Sa.65. Biosimulations Predict Optimal Oral Insulin/Anti-CD3 and Oral Insulin/Exendin-4 Combination Treatment Regimens for the Reversal of Diabetes in the Non-Obese Diabetic (NOD) Mouse

Cited by 4 publications

References 0 publications

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

An in silico exploration of combining Interleukin-12 with Oxaliplatin to treat liver-metastatic colorectal cancer

CD8 + T cell response to adenovirus vaccination and subsequent suppression of tumor growth: modeling, simulation and analysis

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