Researchers at the University of Michigan, USA, discovered that neutrophils may play a key role in cytokine release syndrome (CRS), the life-threatening activation of the immune system which is a common side-effect of CAR-T therapy.
The researchers are now conducting further studies to investigate whether common drugs could be applied to tackle CRS.
CRS is very common among patients receiving CAR-T therapy, and up to 20% of patients may experience severe illness, including multi-organ failure.
The study found that the process of ‘NETosis’ may contribute to the syndrome. During NETosis, neutrophils eject DNA and create webs, designed to catch bacteria.
In the study, published in Blood Advances, the researchers measured various proteins in the blood of patients who received CAR-T therapy, at different timepoints including before, during, and after treatment. They compared the levels of these proteins between patients who went on to develop CRS with those who didn’t.
In the process, the team identified several protein biomarkers that potentially indicated risk of CRS, including a few which were related to neutrophils and NETosis.
Researcher Professor Muneesh Tewari said: “We don’t yet know why, but in some patients, their neutrophils are already triggered and on high alert. They’re already forming these nets, which activates the entire immune system and makes their bodies more prone to over-react by making a flood of cytokines, producing CRS.
“We identified biomarkers that are part of the ‘nets’ the neutrophils cast, and an indication that CRS is likely to occur. In addition to this strong correlation, we hypothesise that NETosis is also contributing to the development of CRS. We want to test this idea in preclinical models, and eventually in clinical trials, to see if we can inhibit the net formation and reduce the risk of CRS in patients.”
One of the drugs that might moderate neutrophils is disulfiram, which is currently used to treat alcohol abuse. The researchers plan to test their theory in preclinical models.
Source:
Flora C, Olesnavich M, Zuo Y, Sandford E, Madhukar R, Rozwadowski M, Sugur K, Ly A, Canbaz AA, Shedeck A, Li G, Geer MJ, Yanik GA, Ghosh M, Frame DG, Bonifant CL, Jain T, Knight JS, Choi SW, Tewari M. (2024) “Longitudinal plasma proteomics in CAR T–cell therapy patients implicates neutrophils and NETosis in the genesis of CRS.” Blood Advances, 14 March 2024, doi: 10.1182/bloodadvances.2023010728
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