How Early VCU Health Clinical Trials Tackled COVID-19’s Cytokine Storm

Editor’s Note: This story is excerpted from a feature published in the winter issue of NEXT magazine. Read the full story in our digital version of the magazine.

When scientists look at the subset of COVID-19 patients who become seriously ill and require hospital support, they are finding a common denominator — an overactive inflammatory response called cytokine release syndrome, or a cytokine storm.

Inflammation is a normal part of the body’s response to infection or injury; however, problems occur when certain diseases trigger an extreme inflammatory response and the body doesn’t shut this cycle off appropriately. The inflammation can become a bigger problem than the original infection because it starts damaging healthy tissue.

“The lungs are quite susceptible to this type of damage,” said Benjamin Van Tassell, Pharm.D., vice chair for Clinical Research and professor in the Department of Pharmacotherapy & Outcomes Science at the VCU School of Pharmacy. “The novel coronavirus seems to be particularly good at pushing people into that aggressive immune response that causes acute respiratory distress syndrome, more quickly than other types of infections, and that may be responsible for the majority of deaths that have occurred.”

Antonio Abbate, M.D., Ph.D., the James C. Roberts Esquire Professor of Cardiology in the VCU School of Medicine explained, “Early on, the COVID-19 data coming from China and Europe showed that patients who had an exaggerated inflammatory response were doing worse. These patients had elevated levels of cytokines in their blood. This reminded clinicians and investigators of the cytokine release syndrome seen relatively rarely as a viral complication, mostly in children, and also after certain types of cancer treatments. These exaggerated levels of cytokines can be mitigated by using cytokine blockers, so that suggested a way to treat this.”

The Cytokine Storm

Cytokines can signal the body to perform a wide variety of functions to fight infection, which include raising temperature, increasing heart rate, formulating blood clots, and mass-producing white blood cells or other types of cells and moving them to the area of infection or injury.

“Cytokines are the messenger proteins that activate other cells and processes to start the immune response,” Dr. Van Tassell said. “They are most active in the damaged tissue, but they can get in the bloodstream and spark a system-wide response.”

This system-wide overreaction is a cytokine storm — when an infection causes an excessive number of cytokines to be produced, which then starts an exaggerated and damaging inflammatory response throughout the body. If cytokine processes aren’t modulated correctly by the immune system, they can start damaging the body by killing healthy cells as well. In vulnerable cases, a very high fever unchecked can cause neurological damage, a high heart rate that can’t be controlled can cause myocardial injury, too many blood clots or an excessive number of white blood cells flooding an area can lead to organ damage or failure.

The lungs are affected by cytokine storms when an excessive amount of white blood cells and fluids flood the area and damage tiny sacs called alveoli that make up the alveolar-capillary barrier. This barrier manages the exchange of gases in the lung by preventing air bubbles from entering the blood stream and fluid from accumulating in the lung. When the alveoli are damaged, the lung can’t clear fluid and the patient struggles to breath. As oxygen levels fall, patients may not only need supplemental oxygen through a mask, but also a ventilator to support their breathing.

The Canakinumab Trial

Prior to COVID-19, clinicians researched a variety of inflammatory conditions to find ways to turn down the body’s excessive immune response. One area of promise has been looking at ways to block cytokines and stop the inflammatory chain reaction early in the process including blocking Interleukin-1ß, a cytokine that activates very early in the inflammatory process.

“Interleukin-1ß, cloned by Charles Dinarello, M.D., more than 35 years ago, is known as the fever molecule. It is a master regulator of the acute and chronic inflammatory response inducing the synthesis and release of thousands of secondary mediators of the inflammatory and coagulation cascade,” Dr. Abbate said.

Clinicians have found success in neutralizing interleukin-1ß with a drug called canakinumab that is already approved to treat auto-inflammatory conditions, such as juvenile arthritis. Canakinumab contains a monoclonal antibody that has been engineered to recognize and bind to interleukin-1ß to prevent it from attaching to other cell receptors and thus interrupting its signaling ability.

In April 2020, Novartis, the manufacturer of canakinumab, announced plans to begin a multicenter, Phase III clinical trial, called the CAN-COVID trial, to examine the efficacy of using canakinumab as an interleukin-1ß blocker to treat cytokine release syndrome in people with COVID-19 pneumonia. The following day, VCU announced it was selected as one of the first sites in the world to begin the CAN-COVID trial at VCU Health, with Dr. Abbate as the principal investigator. Novartis randomized 450 patients worldwide to canakinumab or placebo in the CAN-COVID trial, and VCU Health was the top enrolling site in the world.

“Dr. Van Tassell and I have a lot of experience working with IL-1ß blockers and have done a number of trials looking at how these blockers might affect heart failure and acute myocardial infarction. We are familiar with this drug and have partnered with Novartis before, which made our selection as a test site for this trial a natural fit,” Dr. Abbate said.

For the last 12 years, Drs. Abbate and Van Tassell have studied the effects of inflammation on heart disease. “In heart disease, there are injuries to different parts of the cardiovascular system that trigger an inflammatory response,” Dr. Van Tassell said. “The inflammatory system is designed to put the body on alert, but most of that inflammation may be inappropriate. The larger the inflammatory activation during the heart attack, the worse the outcome is going to be. We’ve spent the last decade figuring out ways to dial down that inflammatory response and promote recovery.

“The inflammatory system is a very complicated process with hundreds of different mediators. One approach is to turn everything off. Our group has been focused on going after certain parts of that inflammatory cascade to be more selective in what we’re turning off. We’ve focused on interleukin-1ß because it sits at the top of the inflammatory cascade. Of all the anti-inflammatory treatments, it seems to be the safest. If you suppress the inflammation too much, you might suppress the immune system and make people more susceptible to infections. IL-1ß blockers have a great track record of hitting the sweet spot — getting the inflammation down without causing immunosuppression.”

The VCU Health team also consulted often with experts in Italy and France to review their early data, including a former fellow from Pauley Heart Center, Dr. Nicole Potere at the University of Chieti and Pescara in Italy. “Those preliminary findings suggested that IL-1ß blockers reduced the severity of disease and mortality rate in patients with COVID-19 pneumonia. We knew this was the right drug to test,” Dr. Abbate said.

Dr. Abbate shared that results of a United Kingdom study using the steroid dexamethasone became available during the CAN-COVID trial, which demonstrated the benefits of a broad-spectrum steroid in severe and critical COVID-19 pneumonia patients. When this data became available, dexamethasone became standard of care and patients without contraindications received it. The U.K. study of dexamethasone supported the overall hypothesis that uncontrolled inflammation is harmful and provides an initial effective anti-inflammatory therapy to reduce mortality.

If you would like to support COVID-19 research like this at VCU Health, please consider making a donation to the VCU Health COVID-19 Response Fund at www.support.vcu.edu/covidresponse.