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Quantitative Systems Pharmacology Modeling of PBMC-Humanized Mouse to Facilitate Preclinical Immuno-oncology Drug Development.

ABSTRACT: Progress in immunotherapy has resulted in explosively increased new therapeutic interventions and they have shown promising results in the treatment of cancer. Animal testing is performed to provide preliminary efficacy and safety data for drugs under development prior to clinical trials. However, translational challenges remain for preclinical studies such as study design and the relevance of animal models to humans. Hence, only a small fraction of cancer patients showed response. The explosion of drug candidates and therapies makes preclinical assessment of every plausible option impossible, but it can be easily tested using Quantitative System Pharmacology (QSP) models. Here, we developed a QSP model for humanized mice. Tumor growth dynamics, T cell dynamics, cytokine release, immune checkpoint expression, and drug administration were modeled and calibrated using experimental data. Tumor growth inhibition data were used for model validation. Pharmacokinetics of T cell engager (TCE), tumor growth profile, T cell expansion in the blood and infiltration into tumor, T cell dissemination from primary tumor, cytokine release profile, and expression of additional PD-L1 induced by IFN-γ were modeled and calibrated using a variety of experimental data and showed good consistency. Mouse-specific response to T cell engager monotherapy also showed the key features of in vivo efficacy of TCE. This novel QSP model, designed for human peripheral blood mononuclear cells (PBMC) engrafted xenograft mice, incorporating the most critical components of the mouse model with key cancer and immune cells, can become an integral part of preclinical drug development.

SUBMITTER: Ma H

PROVIDER: S-EPMC7887858 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The current treatment of Parkinson's disease with dopamine-centric approaches such as L-DOPA and dopamine agonists, although very successful, is in need of alternative treatment strategies, both in terms of disease modification and symptom management. Various non-dopaminergic treatment approaches did not result in a clear clinical benefit, despite showing a clear effect in preclinical animal models. In addition, polypharmacy is common, sometimes leading to unintended effects on non-motor cognitive and psychiatric symptoms. To explore novel targets for symptomatic treatment and possible synergistic pharmacodynamic effects between different drugs, we developed a computer-based Quantitative Systems Pharmacology (QSP) platform of the closed cortico-striatal-thalamic-cortical basal ganglia loop of the dorsal motor circuit. This mechanism-based simulation platform is based on the known neuro-anatomy and neurophysiology of the basal ganglia and explicitly incorporates domain expertise in a formalized way. The calculated beta/gamma power ratio of the local field potential in the subthalamic nucleus correlates well (R (2) = 0.71) with clinically observed extra-pyramidal symptoms triggered by antipsychotics during schizophrenia treatment (43 drug-dose combinations). When incorporating Parkinsonian (PD) pathology and reported compensatory changes, the computer model suggests a major increase in b/g ratio (corresponding to bradykinesia and rigidity) from a dopamine depletion of 70% onward. The correlation between the outcome of the QSP model and the reported changes in UPDRS III Motor Part for 22 placebo-normalized drug-dose combinations is R (2) = 0.84. The model also correctly recapitulates the lack of clinical benefit for perampanel, MK-0567 and flupirtine and offers a hypothesis for the translational disconnect. Finally, using human PET imaging studies with placebo response, the computer model predicts well the placebo response for chronic treatment, but not for acute treatment in PD.

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Quantitative Systems Pharmacology Modeling of PBMC-Humanized Mouse to Facilitate Preclinical Immuno-oncology Drug Development.

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