Case study highlights Parkinson’s-like toxicity after BCMA-directed CAR T-cell therapy
Click Here to Manage Email Alerts
Clinicians who treat patients with chimeric antigen receptor T cells have become adept at identifying and treating acute neurotoxicity, a common adverse event associated with the therapy.
Researchers from Mount Sinai published a case study in Nature Medicine about a patient who developed neurocognitive and hypokinetic movement disorder with features of Parkinson’s disease after receiving ciltacabtagene autoleucel (Janssen, Legend Biotech). The patient received the therapy — a B-cell maturation antigen (BCMA)-targeted CAR-T in development as a treatment for advanced multiple myeloma — as part of the CARTITUDE-1 clinical trial.
Because reports of this toxicity have not been observed with CD19-directed CAR T-cell therapies for other blood cancers, it appears to be specifically associated with BCMA-directed CAR-T, according to study author Samir Parekh, MD, professor of medicine and oncological sciences and director of translational research in myeloma at Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai.
Perhaps more concerning, Parekh and colleagues found that BCMA is expressed on certain cells within the brain, and they saw evidence that BCMA-targeted CAR T cells entered the patient’s cerebrospinal fluid and crossed the blood–brain barrier.
“We put together the report because we felt it was important to educate other physicians who are treating multiple myeloma with CAR-T, as well as patients and companies that are making CAR-T products, because this is a potential [adverse] effect that could be seen more frequently in the future,” Parekh told Healio.
With ciltacabtagene autoleucel poised to become the second BCMA-directed CAR-T to gain commercial approval sometime later this year, clinicians need to discuss the benefits and potential risks of the therapy with their patients, Parekh said. They also must be vigilant about screening for late neurologic toxicities until researchers can make improvements to newer CAR-T constructs to mitigate the risk, he added.
Healio spoke with Parekh about the case study and why the findings are important to the clinical and research communities.
Healio: What made this patient unique compared with others you had treated with BCMA-directed CAR T cells?
Parekh: This patient underwent treatment at Mount Sinai for several years and received CAR T-cell therapy for multiple myeloma. About 3 months after infusion, he came to our clinic reporting symptoms such as tremors, fatigue and the inability to complete routine tasks. We examined him and found some neurologic issues, including tremors and gait changes. We referred the patient to two independent neurologists who concluded he exhibited features of Parkinson’s disease.
During a subsequent test, we found he had circulating CAR T cells in his cerebrospinal fluid. This was unexpected. Examination of the patient’s blood showed very high levels of CAR T cells in circulation. Previous experience suggests that CAR T-cell levels decline precipitously 3 months after infusion to the point where they are barely detectable in most patients. This indicated something unusual, both about the patient and that CAR T cells were infiltrating cerebrospinal circulation. Our group attempted to kill off the CAR T cells using several methods without success. Despite our best efforts, the CAR T cells remained in circulation, and the patient developed sepsis and died.
Healio: What did further analysis show about how the CAR-T functioned within this patient?
Parekh: A subsequent autopsy performed by our neuropathologists showed that the caudate nucleus — part of the basal ganglia and important for motor control — was destroyed and showed evidence of widespread fibrosis. Subsequent staining showed rich infiltration of T cells, which are not normally found in cerebrospinal fluid. This suggests the T cells entered the brain by crossing the blood-brain barrier. Because there were no myeloma cells in the patient’s brain, finding T cells there suggested that some of the cells were expressing a target antigen. The target in this case is BCMA, which is usually seen in plasma cells, B cells and myeloma cells.
We tested for BCMA expression and found it in both the patient’s caudate nucleus and frontal lobe. Our group also examined a few normal control brains to determine if expression of BCMA was limited to specific cases or more universal. To our surprise, brains from patients who did not receive CAR T-cell therapy or had multiple myeloma expressed BCMA, both in the caudate nucleus and the frontal lobe.
Healio: Is this toxicity you observed specific to this class of CAR T cells?
Parekh: We tried to figure out whether this was a generalizable phenomenon. First, we looked at online databases, such as the Allen Brain Atlas, which was established by Microsoft cofounder Paul Allen. It is a lovely database for neurologists and allows them to look at genes known to be expressed in certain parts of the brain. To our surprise, the Allen Brain Atlas confirmed previous knowledge of BCMA being expressed in the caudate of normal brains.
We also examined results from clinical trials for BCMA-directed CAR T-cell therapies and found reports of this type of neurocognitive disorder with Parkinson’s-like symptoms among those who received ciltacabtagene autoleucel and idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio). It was observed in just a handful of patients, likely fewer than 5%. But mention of this treatment-related toxicity is included on the product insert for idecabtagene vicleucel. Based on the science we have reviewed thus far, I think this may be a class effect of CAR-T and perhaps even T-cell receptor therapy that some patients may experience because of the expression of BCMA that we found, not just in our patient's brain but also in other brains.
Healio: How well-known is this toxicity?
Parekh: This phenomenon of neurocognitive and movement disorder with Parkinson’s-like symptoms is not well-known or extensively described in published research. There has been limited discussion of this toxicity in reports on idecabtagene vicleucel and ciltacabtagene autoleucel; however, more focus has been on the acute neurotoxicity known as immune effector cell-associated neurotoxicity syndrome (ICANS), which is well-understood among clinicians who treat patients using CAR T cells.
But this toxicity is very different from ICANS, and I want to make sure clinicians understand this is not the same neurotoxicity that is observed when cytokines are released as CAR T cells proliferate. This Parkinson’s-like neurotoxicity was progressive and started almost 3 months after the initial CAR-T infusion.
Healio: What can be done to detect this toxicity?
Parekh: One of the common characteristics of patients who are developing this type of neurotoxicity is higher disease burden. There is increased attention on preventing neurotoxicity through better patient selection — for example, by trying to reduce tumor burden before patients receive CAR-T. Sometimes this type of careful patient selection is possible, but not always. When possible, there needs to be a discussion between the physician and patient regarding the risks versus benefits. Patients with a higher disease burden must be carefully monitored. So far, they generally experience higher CAR-T levels that stay elevated longer.
Besides the monitoring of CAR T-cell levels, clinicians can conduct more simple tests during the post-CAR-T monitoring period, such as a handwriting evaluation. If treating physicians see any changes, they can consider aggressive treatment with steroids or other available therapies to mitigate the effects before damage is done to the brain.
Healio: Will this toxicity be difficult for clinicians to detect given it occurred outside the normal post-CAR-T intensive monitoring period?
Parekh: That is a concern, but I'm hoping the publication of reports like ours will help inform clinicians to watch out for symptoms that occur even outside the acute-care period. If these symptoms do occur, clinicians should refer their patients to a neurologist for a more aggressive examination to deal with any issues before it is too late.
Healio: What are the clinical implications of this toxicity with regard to use of BCMA-directed CAR-T?
Parekh: There are implications for both the clinical care use and design of future CAR-T. The clinical implications are better patient selection, perhaps more use of cytoreductive therapy to reduce disease burden before patients receive CAR-T, and increased monitoring of patients after infusion. Because this phenomenon of BCMA being expressed in the brain is not well-known, the next generation of CAR-Ts that target BCMA should be built in a smarter way, perhaps being engineered to include features that can kill off the CAR T cells. Or perhaps newer-generation therapies can have dual antigen targeting where they attack plasma cells that express BCMA but not neurons that express the antigen. Therapeutics also can be deployed that block T cells from crossing the blood-brain barrier. These are all possible design issues that could be considered to make the next generation of BCMA-directed CAR T-cell therapy safer.
For more information:
Samir Parekh, MD, can be reached at Icahn School of Medicine at Mount Sinai, Division of Hematology and Medical Oncology, Hess Center — 1470 Madison Ave., New York, NY 10029; email: samir.parekh@mssm.edu.
Collapse
Click Here to Manage Email Alerts