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

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.