PhD Math Defence: Models of Cytokine Dynamics During Cytokine Storms and Synergy During Virus and Drug Combination Therapy

Marianne Waito, Ph.D. Thesis Defence

This thesis presents two mathematical models that aim to support biological researchers in the fight against cancer. They are based on biological phenomena observed by researchers at the Ontario Veterinary College (OVC). The first models interactions of cytokines during a fatal cytokine storm, while the second models effects of combining an oncolytic virus and an epigenetic modifier.

Cytokine storms are a potentially fatal exaggerated immune response consisting of an uncontrolled positive feedback loop between immune cells and cytokines. The dynamics of cytokines are highly complex and little is known about specific interactions. Researchers at the OVC have encountered cytokine storms during virotherapy. Multiple mouse trials were conducted where a virus was injected into mice with varying numbers of leukocytes lacking expression of the type I interferon receptor. In each case a rapid, fatal cytokine storm occurred. A nonlinear differential equation model of cytokine quantities was produced to obtain some information on the common pathways and mutual interactions. Results provide insight into the complex mechanism that drives the storm and possible ways to prevent such immune responses.

Combination therapy is a common technique used by many medical professionals. The intention of these therapies is to create synergistic effects in order to effectively treat disease while simultaneously reducing treatment costs, side effects and dose amounts. Synergy between drug-drug combinations is well classified, having three verified methods of classification. Synergistic effects from combining a virus and a drug however require different classification schemes. Researchers at the OVC are testing multiple virus-drug combinations on two types of mouse acute leukemia cells for their therapeutic effects. An enzyme kinetic model of the individual and combined virus and drug doses was produced to obtain information on the effects of individual versus combination therapies. Results provide insight into combination effects, pinpointing the desired synergistic effects for further biological investigation.

A copy of the thesis is available (in PDF) from Susan McCormick for examination and comment.