BK Virus-Specific T Cells May Be an Effective Option to Treat Progressive Multifocal Leukoencephalopathy

In patients with progressive multifocal leukoencephalopathy (PML), BK virus-specific T-cell infusions have been shown to clear JC virus in the cerebrospinal fluid (CSF) and relieve clinical symptoms, according to results of a study by Muftuoglu et al.

PML is a demyelinating infection caused by JC polyomavirus in patients with impaired immunity. PML can cause altered mental status, ataxia, and visual symptoms, and it usually becomes fatal if disease progression occurs.

Although antiviral medications and mirtazapine were tried, no effective treatment for PML currently exists aside from restoration of a working immune system. The JC virus comes from the Polyomaviridae family, a virus family with similar antigens and genetic immunogenicity as the BK virus.

The BK virus, which arises in patients who have undergone stem-cell transplant or other solid organ transplants, has been successfully treated with viral-specific T cells. Because of their similarities, the research team predicted that they may also work against the JC virus.

Three patients with PML were given T cells targeting BK virus. Patient 1 was a 32-year-old woman who underwent double cord-blood transplantation. After 20 months, the patient developed symptoms of weakness of her left side, slurred speech, confusion, and an inability to stand unaided. Magnetic resonance imaging (MRI) provided findings consistent with PML, and a lumbar puncture revealed JC virus load in the CSF.

Patient 2 was a 73-year-old woman with polycythemia rubra vera who was being treated with ruxolitinib. After a 6-month period of progressive confusion, an MRI examination also found findings consistent with PML. JC viral load in the CSF was 230,000 copies per milliliter.

Patient 3 was a 35-year-old man with AIDS who discontinued antiretroviral therapy due to intolerable adverse events. The patient presented with progressive dysarthria, dysphagia, and ataxia, and MRI examinations revealed findings consistent with PML. The CSF contained JC virus, and CD4 counts were as low as 19 per cubic millimeter. Antiretroviral therapy was restarted, and CD4 counts increased to 147 to 182, but JC viral loads were still present.

In this phase 2 study, each patient’s CSF was examined before each infusion of BK virus-specific T-cell infusion to measure JC viral load. BK virus-specific T-cell infusions occurred every 4 weeks until JC virus was cleared. After the first infusion, all 3 patients had reductions in JC viral load in the CSF. For patient 1, neurologic symptoms were completely resolved except for slight dysarthria, and the size of the white-matter lesions had decreased. For patient 2, neurologic symptoms and signs stopped progressing, and MRI findings revealed immune reconstitution inflammatory syndrome (IRIS). Patient 3 also had major improvements and was able to sit unaided, had better coordination, and presented with IRIS on MRI examination.

Patient 1, after 2 additional infusions, was cleared of the JC virus and remained asymptomatic at 24 months after the last infusion. Patient 2 did not have further improvements in clinical status even after a reduction in JC viral load and died 8 months after the first infusion. Patient 3, after receiving 3 additional infusions, was cleared of the JC virus, and 9 months after the first infusion, was able to walk independently and only had minimal dysarthria.

PML is an infection in patients with defective immunity that have minimal treatment options. In this study, BK virus-specific T cells have shown to be effective in treating these patients and decreasing JC virus loads. Further followup and future studies will be required to determine if this method creates durable responses.

Reference

Muftuoglu M, Olson A, Marin D, et al. Allogenic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451. doi: 10.1056/NEJMoa1801540.