Neurodegenerative biomarker may predict CAR T-cell therapy-related neurotoxicity
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A blood test may predict which patients are predisposed to developing treatment-related neurotoxicity after chimeric antigen receptor T-cell therapy infusion, according to researchers.
Investigators at Washington University School of Medicine in St. Louis — who performed a cross-sectional study of 30 patients — determined levels of a protein called neurofilament light chain (NfL) before and for the month after CAR-T appeared elevated among patients who subsequently developed immune effector cell-associated neurotoxicity syndrome (ICANS).
Elevated NfL levels are evidence of prior damage to neurons, according to Omar H. Butt, MD, PhD, instructor in medicine at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. Although researchers could not determine the origin of the damage among the patients they studied, the elevated NfL levels predisposed them to neurotoxicity related to CAR-T, Butt and colleagues wrote in JAMA Oncology.
“If we can understand who is at risk for complications before we give this treatment, then we can take steps early on to help prevent the effects or reduce the severity of symptoms,” he told Healio.
Butt and co-investigator, Alice Y. Zhou, MD, PhD, oncologist and instructor in the department of medicine at Washington University School of Medicine, spoke with Healio about their research and how the findings may impact ICANS management.
Healio: Can you explain the rationale for evaluating NfL as a potential biomarker to predict neurotoxicity?
Butt: Within the neuro-generation space, there has been a rush of developments in terms of biomarkers for indirectly assaying the quality and health of the brain space. Historically, the predominant approach has been through cerebral spinal fluid. This recently has been extended to blood-based analysis, which has given us an indirect way to quantify the health of the [central nervous system] and what elements of the CNS may have been disrupted. Due to my background as a fellow in this space, I asked some fundamental questions, such as: What's going on in these patients who have this rather severe neurotoxicity syndrome after CAR-T? Are certain markers off and, if so, by how much? Are the changes in any way related to the treatment regimen? How long do these biomarkers remain elevated? This line of questioning motivated the initial experiments driving this study and led us to evaluate the role of NfL in this space.
Zhou: We have a working hypothesis of how neurotoxicity occurs within the blood-brain barrier breakdown, but it does not explain all the factors about why some patients develop neurotoxicity while others do not. We thought there might be a baseline risk that we don't have the resolution yet to detect, so we theorized that some of the neural markers that we know are very sensitive for indicating neuro-degenerative issues — including NfL — might give us a signal of what's going on within patients after they receive CAR T cells.
Healio: How simple is the blood test for NfL, and could any clinician order one to assess levels prior to CAR-T?
Butt: Unfortunately, right now, clinicians cannot order it for this purpose. We are working with several companies and our colleagues in neurology to disseminate knowledge of this in a relatively rapid and easy way to clinicians around the world. That said, the amount of blood that you need for two preparations falls within the standards needed to conduct regular blood work. It doesn't require that much blood. In fact, the sample does not have to be put on ice.
Healio: Has this test been clinically validated?
Zhou: We are working to validate our results in a larger data set. In terms of the test itself, Dr. Butt has been working with the other groups to see if we can make this more accessible, which will require regulatory approval before commercial use.
Butt: The utility of NfL as a biomarker was discovered in published literature on stroke and has historically been used for research purposes in amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The test has been validated for the use within the neurologic space, mostly for ALS. Regardless, NfL level use as a biomarker in neurology is at a point that we know the range of values very well and how to interpret them. We are now in the process of simply trying to repurpose this test for a new use.
Healio: How could a test showing elevated levels of NfL prior to CAR-T effect the course of clinical care?
Butt: You can tailor your clinical approach to sharpen focus on the most at-risk individuals. This can lead to better outcomes, in addition to better resource management and resource utilization.
Zhou: First, you can counsel patients a little bit better about what their post-CAR-T hospital stay will look like. Second, it helps identify who is at higher risk for treatment-related toxicities. Cytokine release syndrome is manageable — we have available treatments. Although ICANS is manageable, it often requires heavy doses of steroids, which can affect the potency of CAR T cells. This means we can be more vigilant in monitoring for ICANS to catch it at its earliest stages and limit the amount of steroids used. This hopefully will prevent escalation to severe ICANS and cerebral edema, which can be fatal.
Some centers provide prophylactic steroids for everyone after CAR-T infusion. Our center does not think this is a useful intervention. However, if we know a patient is at higher risk for developing ICANS, we can provide steroids early at the first sign of symptoms or prophylactic steroids for high-risk patients.
Healio: Do you plan further research on NfL as a biomarker for toxicity related to CAR-T?
Butt: There are two major areas forthcoming. First is trying to understand what exactly is causing the underlying damage that we are quantifying. NfL measures neuro-axonal injury, and anything that causes damage to the brain can cause elevations in this protein. Knowing the underlying source of this injury means we potentially can stop it before it becomes a problem and, therefore, mitigate the risk early.
Second, we hope to get a better sense of what's causing the injury pattern so we can be far more focused in terms of the intervention — as opposed to steroids, which are used as kind of a one-size-fits-all solution to neurotoxicity. Theoretically, addressing the underlying issues causing the damage may mitigate steroid use at a time when clinicians would rather avoid the immune response associated with this intervention.
From a more abstract standpoint, our results thus far emphasize that researchers should not always exist within our own silos and try to include input from experts in other areas. Colleagues in other disciplines may be developing something we could use to our advantage to understand disease pathology.
Reference:
For more information:
Omar H. Butt, MD, PhD, can be reached at omarhbutt@wustl.edu.
Alice Y. Zhou, MD, PhD, can be reached at alice.y.zhou@wustl.edu.
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