A Novel Treatment Approach for PML

Batya Swift Yasgur, MA, LSW

October 19, 2018

Patients with progressive multifocal leukoencephalopathy (PML), which is caused by the JC virus, can be successfully treated using cryopreserved BK-virus-specific T cells, new research suggests.

Investigators treated three patients with PML using an infusion of ex vivo–expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus–specific T cells.

Two patients experienced alleviation of the clinical signs and imaging features of PML as well as a clearing of the JC virus in the cerebrospinal fluid (CSF).

In the third patient, JC viral load was reduced, and the patient's symptoms stabilized. These effects persisted until her death 8 months after the first infusion.

"We were very excited about our results because there's been a lot of interest in cancer immunotherapies, but this is immunotherapy for PML, which is another devastating disease, an infection whose outcomes are sometimes worse than for some patients with cancer," senior author Katayoun Rezvani, MD, PhD, professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News.

"What's attractive about our approach is that the T-cell products are frozen and off the shelf, just like a drug that you can take off the shelf and give to a patient — we can potentially do the same with these cells, just store them and then give them to the patient," she said.

The study was published online October 11 in the New England Journal of Medicine.

Multiple Lines

PML is a rare demyelinating infection of the central nervous system (CNS) caused by reactivation of the JC polyomavirus. It occurs in the context of defective cellular immunity in several underlying conditions, including advanced HIV infection, hematologic and solid-tissue cancers, hematopoietic stem cell transplant, and the use of immunosuppressive drugs, such as the biologic therapies used in multiple sclerosis, the authors write.

JC virus typically causes altered mental status, motor deficits, ataxia, and visual symptoms. JC virus infection is progressive and usually fatal. The only effective treatment for PML that is currently available is restoration of cellular immune function, which is not feasible for many patients.

BK virus, which also belongs to the Polyomaviridae family, causes nephritis and cystitis in patients who have undergone stem cell transplant and in recipients of transplanted solid organs.

The researchers had previously used virus-specific T cells to treat BK virus following stem cell transplant. Given that BK and JC viruses are genetically similar and share sequence homology in immunogenic proteins, they hypothesized that T cells developed against the BK virus may also be effective against JC virus.

"We realized that the T cells generated against BK are also good at recognizing JC, so we looked at three patients, each with a different underlying disease that predisposed them to PML, and gave them T cells generated against BK," Rezvani said.

She noted that these cells can be generated by healthy individuals. About 50% of the population has been exposed to the JC virus, and 80% has been exposed to the BK virus.

"We took T cells of 27 healthy donors, cultured them with peptides derived from immunodominant proteins by virus, then added cytokines, which were growth factors for T cells," she explained.

"After 10 days, we now had T cells that were preferentially grown to recognize the virus. We grew them and picked a line suitable for the patient, based on the patient's HLA tissue type," she continued.

She noted that they were unable to conduct full HLA tissue typing. "But we found a line that was at least partially matched and administered those cells intravenously," she said.

The patients received the BK virus–specific T-cell infusions every 4 weeks until the JC virus was cleared from the CSF.

The most closely HLA-matched T-cell line was selected (ie, ≥1 HLA-A and 1HLA-DRβ1 allele were required to match).

Three Patients

Patient 1, a 32-year-old woman who underwent double cord-blood transplant with myeloablative conditioning for FLT3-positive acute myeloid leukemia 20 months prior to PML symptom onset, presented with left-sided weakness, slurred speech, confusion, dysarthria, and an ataxic gait, and she was unable to stand without being aided.

Her findings on MRI were consistent with PML. A JC virus DNA load of 130 copies per milliliter in her CSF met criteria for a diagnosis of PML.

Despite administration of mirtazapine (Remeron, Organon), a repeat MRI performed 3 weeks later showed progression of the lesions, and the JC viral load had increased to 700 copies per milliliter.

Patient 2, a 73-year-old woman with JAK2-positive polycythemia rubra vera that had been treated with ruxolitinib (Jakafi, Incyte), presented with a 6-month history of progressive confusion, expressive aphasia, blurred vision, and ataxia.

An MRI revealed findings consistent with PML, and her viral load for JC virus in the CSF was 230,000 copies per milliliter.

Patient 3, a 35-year-old man with AIDS who had discontinued highly active antiretroviral therapy (HAART) 5 years earlier, presented with progressive dysarthria, dysphagia, and ataxia. His MRI findings were consistent with PML, and his CSF contained JC virus.

Despite reinitiation of HAART, the symptoms of PML progressed over a 4-month period. MRI revealed enlargement of brain lesions, and JC viral load was increased in the CSF.

Tracking Donor T Cells

After the first infusion, all three patients showed a reduction in the JC viral load in the CSF (from 700 to 78 copies per milliliter in patient 1; from 230,000 to 5200 copies per milliliter in patient 2, and from 4300 to 1300 copies per milliliter in patients 3).

The CD4 cell counts before the T-cell infusion also changed after the first infusion (from 53 to 77 per cubic millimeter; 625 to 743 per cubic millimeter; and 96 to 111 per cubic millimeter, respectively).

Patient 1 experienced complete resolution of neurologic symptoms with the exception of slight dysarthria and a reduction in the size of the white matter lesions on MRI.

In patient 2, progression of the neurologic symptoms and signs stopped. MRI findings were consistent with immune reconstitution inflammatory syndrome (IRIS).

Patient 3 showed clinical improvement and was able to sit unaided, which had not been possible before the infusion. He also showed improvement in dysarthria and better coordination. The MRI findings were consistent with IRIS.

All three patients experienced continued improvement following subsequent infusions.

Patient 1 received two additional infusions, which resulted in complete clearance of JC virus in the CSF and resolution of clinical and imaging findings. These effects were sustained through follow-up 27 months after her first infusion.

Patient 2 received a second infusion, which was associated with further reduction in JC viral load in the CSF, but there was no further improvement in clinical status or imaging findings. She died 8 months after the first infusion.

Patient 3 received three additional infusions, which were followed by complete clearance of JC virus in the CSF and reduction in the size of MRI signal changes.

Clinical signs and symptoms improved. The patient regained independent mobility, was able to walk with a cane, and experienced minimal dysarthria 9 months after the first infusion.

No infusion-related events occurred, and none of the patients developed opportunistic infections during the study period.

The researchers used the HLS-Bw mismatch between patient 1 and her T-cell donor to study the trafficking of virus-specific T cells to the CSF.

The population of donor virus–specific T cells grew to 294 times its original size in the peripheral blood by week 1 after the first infusion.


Approximately 20% of the patient's CD3 cells in the CSF were of donor origin, suggesting that "successful transit of virus-specific T cells to the central nervous system was occurring," the authors state.

The detection of donor virus–specific T cells with effector memory phenotypes in the recipient's CSF "suggested that activated type 1 helped T cells homed to the CSF."

Mass cytometry demonstrated that the donor virus–specific T cells, which were predominantly CD4, "expanded and differentiated in vivo to give rise to multiple subpopulations with phenotypic characteristics of both memory and activated T cells, a finding consistent with an antiviral response," the researchers report.

"In patient 1, we could actually track the fate of the cells we had infused and could show that these donor cells divided and proliferated in the patients, making their way to the patient's CSF," said Rezvani.

"We looked at the CSF and could find high number of donor T cells there, coinciding with the virus going away and the patient's symptoms improving," she said.

Important Shift

Commenting on the study for Medscape Medical News, Richard O'Reilly, MD, professor, Cornell Medical College, and chief, Pediatric Bone Marrow Transplant Service and member, Division of Immunology, Memorial Sloan Kettering Cancer Center, New York City, who was not involved in the study, called it "an important study of a rare complication of severe immunodeficiency [that is] essentially a uniformly lethal infection."

He noted that, "from the standpoint of patients who have had this disorder, historically, their chances of survival were nil; but now, we have an approach that can potentially correct this disease."

In fact, "as far as I can see it, it's the only approach available, so it's a shift," he said.

Rezvani added, "It's important for clinicians to maintain an index of suspicion and look for JC virus when performing a lumbar puncture, since it is typically either underdiagnosed or not diagnosed."

She encouraged clinicians "not to adopt a fatalistic approach, thinking there's nothing we can do, because now we have a clinical trial suggesting an effective approach."

She noted that larger studies with more patients and longer follow-up are necessary, but expressed optimism about the future application of the research to PML patients.

The study was supported in part by an MD Anderson Cancer Center AML

Moonshot Grant and the National Institutes of Health. Discloses of relevant financial relationships are available in the original article at NEJM.org. Dr O ' Reilly has received research funding and royalties from Optera Therpeutics.

N Engl J Med. Published online October 10, 2018. Abstract

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