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Villanova Professor Publishes a “Model-Based Investigation of Cytokine Dynamics in Immunotherapies”

Dr. Jacky Huang, director of the Biological and Environmental Systems Engineering group, with PhD student Brooks Hopkins.
Dr. Jacky Huang, director of the Biological and Environmental Systems Engineering group, with PhD student Brooks Hopkins.

Associate Professor of Chemical Engineering Dr. Jacky Huang’s Biological and Environmental Systems Engineering group recently published a paper in the journal Processes detailing a modeling-based strategy to combat cytokine release syndrome, which is a deadly side effect found in immunotherapy patients whose cytokine levels have dramatically increased. (Cytokine are any of a number of substances, which are secreted by certain cells of the immune system and have an effect on other cells.)

The objective of immunotherapy is to primarily harness a patient’s own immune system to fight the proliferation of cancer and disease. One of the most popular immunotherapies is CAR-T-cell therapy, which aims to provide patient-specific treatment. In CAR-T therapy, the patient’s blood cells are extracted and the T-cells are then isolated and exposed to a viral vector that integrates the coding sequence for a chimeric antigen receptor (CAR). This receptor enables the modified T-cells to attack cancer cells when the T-cells are infused back into the patient’s body.

The year 2017 was a hallmark year for CAR-T-cell therapy with two products gaining FDA approval, including Novartis’s Kymriah (August, 2017) and Gilead’s Yescarta (October, 2017). The products had remarkable complete remission rates of 83% and 51%, respectively, but many patients experienced serious adverse effects of cytokine release syndrome. A marked imbalance in cytokine levels occurs in these patients, with inflammatory and anti-inflammatory cytokines competing with one another, causing a multitude of symptoms ranging from flu-like symptoms to organ failure and death.

Since cytokine release syndrome is a deadly side effect of T-cell therapy, it is crucial to determine the intervention strategy to inhibit cytokines in the therapy. Dr. Huang says, “While experimental investigation for cytokine inhibition may put patients’ lives at risk, a good modelling approach can help generate hypotheses to guide experimental investigation.” With the help of Villanova Engineering PhD student Brooks Hopkins, Dr. Huang’s group studied the uncertainties in cytokine release profiles from an ordinary differential equation model and designed the first quantitative formula to grade the severity of cytokine release syndrome from cytokine profiles. In addition, his group, for the first time, provided a rationale approach to determine the sequential cytokine inhibition targets. These results pave the way for further experimental investigation of cytokine release syndrome.

In addition to the cytokine release syndrome project, Dr. Huang’s group is working on another T-cell therapy project that was recently funded by The National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL). They are collaborating with Dr. William Kelly, director of NovaCell, Villanova’s Center for Cellular Engineering, to study the optimal growth medium conditions for accelerating the growth of T-cells. These T-cell therapy projects expand Dr. Huang’s systems biology research from bacteria (e.g., biofilm-forming foodborne pathogens) to mammalian cells (i.e., T cells).