Abstract

Cancer cells often shed receptors targeted by immunotherapies. Shed receptors can reduce drug efficacy by binding to free drug, preventing its binding to membrane-bound receptors. The goal of this dissertation is to investigate the effects of shed targets on the efficacy of cancer immunotherapies. First, we study liquid tumors by extending a PK/PD model to include receptor shedding, drug-induced enhancement of shedding, drug binding to shed receptors, and drug-induced tumor lysis. We use our model to elucidate the effect of shed target receptors on the efficacy of immunotherapies through uncertainty and sensitivity analyses. Our findings support the claim that the presence of shed target receptors significantly affects drug dynamics at high shed-target-to-dose ratios. Our PK/PD model is constructed as a dynamical system, and we show that its fixed point is a global attractor. Next, we consider the effect of shed receptors on the efficacy of T-cell engagers (a subtype of immunotherapies) in solid tumors by constructing a system of partial differential equations that describe the change in tumor size over time. A T-cell engager is an antibody construct that attaches to a tumor cell on one end and a T cell on the other, allowing the T cell to kill the tumor cell. We included T cells and their receptor states in our model to capture the T-cell engager dynamics. Our model provides a novel mathematical framework for T-cell engagers with and without shedding. We solved our PDE system for different shedding rates and found that increasing the shedding rate decreases the drug penetration in the tumor. The reduced drug penetration that we saw with high shedding resulted in a drastic decrease in drug efficacy. At the end of this dissertation, we discuss ways to enhance our solid tumor model and additional studies that can be conducted.

Publication Date

12-2025

Document Type

Dissertation

Student Type

Graduate

Degree Name

Mathematical Modeling (Ph.D)

Department, Program, or Center

Mathematics and Statistics, School of

College

College of Science

Advisor

David Ross

Advisor/Committee Member

Khamir Mehta

Advisor/Committee Member

George Thurston

Campus

RIT – Main Campus

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