CAR-T drugs and parkinsonism: a cause for concern?

Chimeric antigen receptor (CAR)-T therapy has been linked to serious side effects, following which U.S. regulators issued boxed warnings on the treatment. Now, growing concerns over parkinsonism have led to a clinical trial halt for a CAR-T candidate.

Belgian pharmaceutical Galapagos paused the enrollment of patients in a phase 1/2 trial that began last year. The study was designed to test the safety and efficacy of its CAR-T candidate GLPG5301 in patients with relapsed or refractory multiple myeloma, a type of blood cancer that develops in the bone marrow. The trial was stopped after a patient showed signs of parkinsonism. The condition is characterized by a range of movement symptoms like tremors and muscle rigidity. The most common type is the neurodegenerative condition Parkinson’s disease.

Galapagos to adjust trial protocol amid parkinsonism concerns for CAR-T candidate GLPG5301

While Galapagos didn’t disclose further details regarding the setback in its half-year finance report, it submitted a protocol amendment – making changes to the trial design – and vows to follow patient history more closely in hopes to resume recruiting patients soon.

The candidate GLPG5301 is an autologous – using a patient’s own immune cells – CAR-T therapy that targets the B-cell maturation antigen expressed in B cells in multiple myeloma. GLPG5301 is not the only CAR-T drug to cause worry over parkinsonism-related side effects.

The U.S. Food and Drug Administration (FDA)-approved Carvykti has also been flagged for its link to a risk of developing parkinsonism and another neurological condition called Guillain-Barré syndrome. The package warning states that complications associated with these conditions have led to fatal reactions in the past. The therapy is owned by pharma giant Johnson & Johnson and multinational biopharma Legend Biotech, and was greenlit for multiple myeloma in 2022.

In the phase 3 trial that led to Carvykti’s approval, eight out of 285 patients experienced parkinsonism, with five patients having more severe symptoms of the disease. This was following events of drug-related cytokine-release syndrome (CRS) in patients, a common side effect of CAR-T drug use that occurs when the immune system releases proteins called cytokines into the bloodstream quickly causing inflammation. Some of the parkinsonism symptoms included movement disorders, cognitive impairment, and personality changes.

While Carvykti comes with a boxed warning, Bristol Myers Squibb’s recently-approved CAR-T drug Abecma doesn’t, despite parkinsonism having been reported as an adverse event.

Autoimmune CAR-T trial face scrutiny over neurotoxicity risks

Cancer CAR-Ts aren’t the only drugs that have sparked scrutiny. CAR-T therapies for autoimmune diseases have prompted safety questions too. In a first in a CAR-T trial for an autoimmune disease, a patient was reported to have experienced a potentially life-threatening neuropsychiatric condition called immune effector cell-associated neurotoxicity syndrome (ICANS). Like CRS, ICANS is a neurotoxicity that can occur during immunotherapy treatment.

A patient in a lupus nephritis trial run by American biotech Cabaletta Bio experienced grade 4 ICANS after treatment with the biotech’s CAR-T drug CABA-201. The company now plans to change its protocol to monitor patients more closely and improve safety.

Most CAR-T drugs have a boxed warning for neurotoxicities and most CAR-T-autoimmune studies only enroll patients with severe forms of the disease because the drug poses high risks of side effects. The boxed warnings come after a recent FDA inquiry put these drugs under the microscope. However, as the number of patients affected by these adverse effects is small, the FDA added that the benefits of the drug outweighed the risks.

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