A validated mathematical model of FGFR3‐mediated tumor growth reveals pathways to harness the benefits of combination targeted therapy and immunotherapy in bladder cancer

Abstract

Bladder cancer is a common malignancy with over 80,000 estimated new cases and nearly 18,000 deaths per year in the United States alone. Therapeutic options for metastatic bladder cancer had not evolved much for nearly four decades, until recently, when five immune checkpoint inhibitors were approved by the U.S. Food and Drug Administration (FDA). Despite the activity of these drugs in some patients, the objective response rate for each is less than 25%. At the same time, fibroblast growth factor receptors (FGFRs) have been attractive drug targets for a variety of cancers, and in 2019 the FDA approved the first therapy targeted against FGFR3 for bladder cancer. Given the excitement around these new receptor tyrosine kinase and immune checkpoint targeted strategies, and the challenges they each may face on their own, emerging data suggest that combining these treatment options could lead to improved therapeutic outcomes. In this paper, we develop a mathematical model for FGFR3‐mediated tumor growth and use it to investigate the impact of the combined administration of a small molecule inhibitor of FGFR3 and a monoclonal antibody against the PD‐1/PD‐L1 immune checkpoint. The model is carefully calibrated and validated with experimental data before survival benefits, and dosing schedules are explored. Predictions of the model suggest that FGFR3 mutation reduces the effectiveness of anti‐PD‐L1 therapy, that there are regions of parameter space where each monotherapy can outperform the other, and that pretreatment with anti‐PD‐L1 therapy always results in greater tumor reduction even when anti‐FGFR3 therapy is the more effective monotherapy.

Dysregulated FGFR3 signaling alters the immune landscape in bladder cancer and presents therapeutic possibilities in an agent-based model

“…To focus on the outcome of these simulations and make comparisons to mouse model experiments, we report the model metrics on Day 25, a typical endpoint for the mouse model experiments. Indeed, the in silico growth curves in Figure 2A show similar trends as our previously published mouse model experiments ( 18 ) ( Supplementary Figure 2 ). Using a Gaussian kernel to smooth the outcomes at Day 25, we see that anti-FGFR3 monotherapy does decrease Day 25 tumor burden for tumors with mutants present, as illustrated by the red peaks of the PDFs lying to the left of the black peaks in the middle and right column of Figure 4A .…”

“…In bladder cancer, ODE models have been used to understand immunotherapy response ( 15 – 17 ). We previously analyzed a model of FGFR3 mutation in bladder cancer, considering the therapeutic efficacy of combination ICI and a small molecule inhibitor (SMI) of FGFR3 ( 18 ).…”

Mathematical model predicts tumor control patterns induced by fast and slow cytotoxic T lymphocyte killing mechanisms

“…To predict which patients are more likely to respond to ICIs, and to develop improved therapeutic strategies, understanding the differential cell-kill mechanisms that T cells use against tumor cells is essential. Since the discovery of the PD-1/PD-L1 immune checkpoint, the immunosuppressive effect of the checkpoint has been included in several mathematical models of tumor-immune dynamics 14 , 16 – 18 . While our model has similar features to existing models, our work is distinctive and innovative in two ways: (i) we consider two types of tumor cells (high antigen and low antigen phenotype), and (ii) we explicitly incorporate the two killing mechanisms.…”

Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers

“…Immunotherapy such as anti-PDL1 therapy has been shown to have more effect in FGFR wild-type tumors in bladder cancer cell lines while less effects from immunotherapy were observed in FGFR4-overexpressed gastric cancer cells [144,145]. Patients with FGFR1overexpressed melanoma were also found to have less response to pembrolizumab while FGFR-altered HCC tends to have progressive disease after immunotherapy [146][147][148].…”