Understanding Parkinsonism after CAR T therapy

Doctors at the University of Washington and Fred Hutch Cancer Center have better characterized an emerging complication of chimeric antigen receptor (CAR) T-cell therapy. A recent paper in Movement Disorders Clinical Practice reports four patients who developed parkinsonism as after receiving CAR T-cell therapy in lymphoma and multiple myeloma.

Parkinsonism, which is a general term for symptoms that resemble Parkinson’s disease, manifests as slow movement, tremors, posture instability, and rigidity. While the cause of many cases of parkinsonism or Parkinson’s disease is not fully understood, Parkinson’s disease is characterized by loss of dopamine-producing neurons in the midbrain.

CAR T cells are a patient’s own T cells engineered to attack cancer based on unique molecular markers such as B cell maturation factor (BCMA) in multiple myeloma or CD19 for B cell lymphomas. The cancer-killing power of CAR Ts is incredible but can cause collateral damage in a small subset patients due to immune overactivation and inflammation. One potential side effect is immune effector cell-associated neurotoxicity syndrome (ICANS), which ranges from mild cognitive impairment to severe and sometimes fatal brain inflammation. While traditional ICANS is generally reversible, other neurological complications can be a long-term concern for CAR T recipients. In particular, a spectrum of motor dysfunction and other neurocognitive issues have been reported in rare cases following the BCMA-targeting CAR T-cell therapy known as ciltacabtagene autoleucel (also known as cilta-cel).

“This case series provides extensive phenotypic descriptions of four patients with treatment-emergent or treatment-exacerbated parkinsonism after receiving BCMA- and CD19-targeting CAR T-cell therapy,” says lead author Dr. John Sanderson, a movement disorders fellow in the University of Washington Department of Neurology. “To our knowledge, this is also the first report of parkinsonism with CD19-targeting CAR T therapy.”

Three of the four patients received cilta-cel for multiple myeloma, and the fourth received CD19-targeting axicabtagene autoleucel (axi-cel) for lymphoma. All four patients were men from ages 57-70 who developed cytokine release syndrome, a known risk factor for other complications. Their parkinsonism symptoms developed between 10 and 44 days post-CAR T infusion.

The patients underwent dopamine transporter scans (DaTscan) to evaluate dopamine uptake in the brain. “Two of the patients described had abnormal DaTscans, indicated degeneration in the striatonigral dopaminergic pathway, which is what we typically see in Parkinson’s disease,” explains Dr. Sanderson. “One of these patients had subtle symptoms of Parkinson’s disease before undergoing CAR T therapy while the other did not.”

The patient who exhibited parkinsonism symptoms had been evaluated by a neurologist about a resting tremor a year before beginning CAR T treatment. He received anti-CD19 axi-cel and observed the tremors worsening 10 days post-treatment.

“This suggests that CAR T therapy may unmask underlying pre-clinical Parkinson’s disease, and highlights the need for careful screening before treatment,” says Dr. Sanderson.

In addition to the need for better screening practices, more work is necessary to understand why CAR T causes neurological side effects. While CAR T neurotoxicity is often thought to be due to off-target effects, some have proposed that BCMA or CD19 may be expressed in rare neurons and causing on-target killing.

This report “highlights the need to understand the mechanism of this adverse effect,” says Dr. Sanderson. “Is there a specific proclivity for CAR T cells to target the brain structures associated with parkinsonism or is it less specific effect of systemic stress? Is it a class effect, or does the antigen target of the CAR T therapy modulate the risk of developing parkinsonism?”

While there is no such thing as a perfect anti-cancer drug, CAR T therapy has been a leap forward in the treatment of many challenging cancers. As such, their use will continue to expand as existing therapies are adapted for other conditions and new CAR T therapies are developed. It is crucial that physicians understand possible adverse effects like parkinsonism so they can anticipate, prevent, and treat issues to the best of their ability.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Andrew Portuguese, Jordan Gauthier, and Rahul Banerjee contributed to this research.

No specific funding was received for the spotlighted research.

Sanderson JB, Lin YH, Su K, Wang Y, Portuguese A, Gauthier J, Durbin M, Banerjee R. 2025. Treatment-Emergent Parkinsonism in Four Patients Treated with Chimeric Antigen Receptor T-Cell Therapy. Mov Disord Clin Pract. doi: 10.1002/mdc3.70452.