When white blood cells, designed to defend the body against infection, become excessively activated, they release their DNA into nets, further disrupting the immune system and increasing the likelihood of patients developing a potentially severe reaction to immunotherapy. A recent study conducted by the University of Michigan Health Rogel Cancer Center has revealed a link between the most common type of white blood cells, which serve as the body’s primary defense in the immune system, and a serious complication of CAR T-Cell immunotherapy. The results, published in Blood Advances, demonstrate a process known as NETosis, a process in which neutrophils release their DNA to form webs, might play a role in the onset of cytokine release syndrome (CRS), an overly active immune system response that can be life-threatening.
Additionally, a group of researchers, led by Muneesh Tewari, M.D., Ph.D., and Sung Won Choi, M.D., M.S., have discovered specific proteins that serve as biomarkers for NETosis and could potentially forecast the likelihood of CRS development in patients before any symptoms appear.
Tewari explained that the team’s findings could have significant implications for early detection and management of CRS.The author explains that there are FDA-approved medications that can impact neutrophils, such as disulfiram, which is used to treat alcohol abuse. While these drugs are usually prescribed for other conditions, they could potentially be used to inhibit NETosis and prevent CRS.
“We have identified biomarkers that are part of the ‘nets’ that neutrophils release, and evidence that CRS is likely to occur,” Tewari explained. “In addition to this strong connection, we believe that NETosis also contributes to the development of CRS. We aim to test this theory in preclinical models, and eventually in clinical trials, to see if we can prevent net formation and reduce the risk.Patients developing cytokine release syndrome (CRS) is a common occurrence, with over 70% of patients experiencing it. Approximately 15%-20% of these cases are considered severe, potentially leading to admission to an intensive care unit due to symptoms such as low blood pressure, elevated heart rate, difficulty breathing, or organ failure. CRS can manifest within a week of receiving CAR T-cell infusions, and little is known about the underlying mechanisms during this initial period before symptoms appear. To gain more insight, the research team utilized proteomics analysis to evaluate numerous proteins in blood samples from patients.The researchers studied patients who received CAR T-cell therapy, including those who experienced CRS and those who did not. “We identified numerous proteins that appear to be different in patients who develop CRS compared to those who do not. We also discovered fewer than 10 proteins that appeared to be different before patients developed CRS, even before receiving the treatment,” Tewari stated. The team also examined how the proteins in the blood plasma changed as CRS developed over time. “We observed an increase in neutrophil-related proteins, which led us to focus more on neutrophils specifically, ultimately leading us to NETosis.”Tewari explained. The process of NETosis is similar to its name. When neutrophils are activated, such as at the start of a bacterial infection, they release their tightly packed DNA from the nucleus into net-like structures that can capture and contain the bacteria. In patients who develop CRS, Tewari clarified that although there is no actual bacteria present, the neutrophils behave as if there is an invader. It is still unknown why, but in some patients, their neutrophils are already activated and on high alert, forming these nets.the activation of the entire immune system, leading to an over-reaction and flooding of cytokines, causing CRS.”
Furthermore, Tewari is also looking into clinical trials to determine if specific FDA-approved medications can help control NETosis. He believes that this research could provide insights into the impact of stress on the body at a cellular level. Tewari emphasized, “We are increasingly recognizing the significance of an activated immune system in terms of outcomes, particularly in relation to cytokine release syndrome.”
He added, “Preliminary data suggests that psychological stress may impact neutrophil function. This study is just one piece of the puzzle that may contribute to a greater understanding of the connections between stress and immune response.”The article presents further insights into the negative impact of stress on the body and its contribution to illness. The study published in Blood Advances suggests that neutrophils and NETosis play a role in the development of CRS in CAR T–cell therapy patients. The researchers conducted longitudinal plasma proteomics to support their findings.
