White blood cell 'nets' may signal early immunotherapy complication

When white blood cells, designed to shield the body from infection, are overly stimulated, they release their DNA into webs, further disorganizing the immune system and increasing the risk of a severe reaction to immunotherapy. Research from the University of Michigan Health Rogel Cancer Center has uncovered a link between the most prevalent type of white blood cell and a critical side effect of CAR T-Cell therapy.

Published in Blood Advances, the study reveals that a phenomenon called NETosis, where neutrophils release their DNA to form nets, might be instrumental in causing cytokine release syndrome (CRS). CRS is a potentially deadly hyperactivation of the immune system. The researchers, led by Dr. Muneesh Tewari and Dr. Sung Won Choi, discovered specific proteins that serve as biomarkers for NETosis and could predict which patients might develop CRS before symptoms emerge.

Dr. Tewari mentions that drugs approved by the FDA, such as disulfiram used to treat alcohol dependency, could be repurposed to target neutrophils. These medications might inhibit NETosis and thus prevent CRS. "We identified biomarkers within the neutrophil nets that suggest CRS is imminent," Tewari said. "We hypothesize that NETosis contributes to CRS development. We aim to test this in preclinical models and clinical trials to see if preventing net formation reduces CRS risk."

More than 70% of patients undergoing CAR T-cell therapy develop CRS, with 15%-20% of these cases being severe enough to necessitate intensive care due to complications like low blood pressure, rapid heart rate, respiratory issues, or organ failure. CRS can manifest within a week after CAR T-cell treatment. Tewari points out that the mechanisms at play during this initial week are not well understood. To fill this knowledge gap, the team employed proteomics analysis to scrutinize hundreds of proteins in blood samples from patients who received CAR T-cell therapy, comparing those who developed CRS to those who did not.

"We found dozens of proteins that differ between patients who develop CRS and those who don’t. Before CRS symptoms appeared, we identified fewer than ten proteins that differed," Tewari elaborated. The team further examined how proteins in blood plasma fluctuate as CRS evolves. "Neutrophil-related proteins started to rise, which led us to focus on neutrophils and the NETosis process," Tewari said.

NETosis occurs when neutrophils, usually activated by bacterial infections, release their tightly packed DNA into nets that can capture bacteria. In CRS patients, though there's no actual bacterial threat, neutrophils react as if there is. "We don't know why, but some patients' neutrophils are already in a heightened state, forming these nets, which triggers the whole immune system, leading to an overproduction of cytokines and CRS," Tewari explained.

Besides pursuing clinical trials to test if existing FDA-approved drugs can curb NETosis, Tewari believes the study offers insights into how stress affects cellular functions. "Our findings show that an overactive immune system impacts outcomes, particularly concerning CRS," Tewari said. "Preliminary data suggests psychological stress can alter neutrophil function. This study adds to our understanding of how stress can adversely affect the body and contribute to diseases."