An in silico Model of T Cell Infiltration Dynamics Based on an Advanced in vitro System to Enhance Preclinical Decision Making in Cancer Immunotherapy.

Autor:	Lewin TD; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Avignon B; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Tovaglieri A; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Cabon L; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Gjorevski N; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland., Hutchinson LG; Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2022 May 02; Vol. 13, pp. 837261. Date of Electronic Publication: 2022 May 02 (Print Publication: 2022).
DOI:	10.3389/fphar.2022.837261
Abstrakt:	Cancer immunotherapy often involves the use of engineered molecules to selectively bind and activate T cells located within tumour tissue. Fundamental to the success of such treatments is the presence or recruitment of T cells localised within the tumour microenvironment. Advanced organ-on-a-chip systems provide an in vitro setting in which to investigate how novel molecules influence the spatiotemporal dynamics of T cell infiltration into tissue, both in the context of anti-tumour efficacy and off-tumour toxicity. While highly promising, the complexity of these systems is such that mathematical modelling plays a crucial role in the quantitative evaluation of experimental results and maximising the mechanistic insight derived. We develop a mechanistic, mathematical model of a novel microphysiological in vitro platform that recapitulates T cell infiltration into epithelial tissue, which may be normal or transformed. The mathematical model describes the spatiotemporal dynamics of infiltrating T cells in response to chemotactic cytokine signalling. We integrate the model with dynamic imaging data to optimise key model parameters. The mathematical model demonstrates a good fit to the observed experimental data and accurately describes the distribution of infiltrating T cells. This model is designed to complement the in vitro system; with the potential to elucidate complex biological mechanisms, including the mode of action of novel therapies and the drivers of safety events, and, ultimately, improve the efficacy-safety profile of T cell-targeted cancer immunotherapies. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Lewin, Avignon, Tovaglieri, Cabon, Gjorevski and Hutchinson.)
Databáze:	MEDLINE
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