The researchers report that adoptive transfer of donor-derived anti-polyomavirus-specific T-cells (PyVSTs) was safe in a small number of patients with refractory PML.
"We think this strategy has real potential to be one of the first treatments for PML," Erin Beck, MD, PhD, from the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, said here at a press conference.
Beck presented the work on behalf of colleagues including lead author Irene C.M. Cortese, MD, from the National Institutes of Health in Bethesda, Maryland, here at the American Academy of Neurology (AAN) 2019 Annual Meeting.
"Our study focused on those patients for whom immune restoration is impossible or too slow and who really have an otherwise dismal prognosis," Beck said. These included patients with genetic immunodeficiencies, hematologic malignancies, and autoimmune diseases on drugs that were hard to reverse or slow to stop working.
"Our strategy, which was developed with colleagues in transplant medicine at the National Heart, Lung, and Blood Institute, was to borrow, basically, immune cells from first-degree relatives of our patients," she explained.
Using peptide libraries derived from BK large T (LT) and viral protein 1 (VP1) that are highly cross-reactive with the structurally homologous JC proteins, they generated PyVSTs from partially matched first degree relatives of these patients with PML.
"Patients initially received 1 x 106 PyVST cells/kg, followed by up to two additional infusions at 2 x 106 PyVST cells/kg, a minimum of 28 days apart," they write.
The safety monitoring period was 28 days after each infusion. Serial MRI and lumbar punctures were performed to monitor response for 12 months following the last infusion, the researchers note.
Twelve patients, all with worsening disease at the time of treatment, received at least one infusion. No serious treatment-related adverse events were seen, including no overt cases of immune reconstitution inflammatory syndrome (IRIS), a reaction that can itself be fatal, Beck noted.
Five patients died of refractory PML, four of whom died longer than 30 days following the last infusion. Seven patients stabilized, some with significant neurological improvement, the researchers report.
"This was encouraging for us because these patients, as I said, were worsening at the time of their treatment and we did not expect them to do well," she said.
Two of the PML survivors subsequently died of their underlying condition 1 year after the last infusion, the authors said.
"In addition to doing the study, we've also been able to look at some of the qualities of the cells, and the donors of the cells, to give us some insight into what are important factors to maximize the antiviral activity of the cell product and that we think can be used to further optimize this kind of therapy in the future," Beck concluded.
This same group published observational outcomes in the New England Journal of Medicine on April 10 of work using the PD-1 inhibitor pembrolizumab for the treatment of PML (N Engl J Med. 2019;380:1597-1605).
A small number of patients received treatment on a compassionate basis, so it was not designed as a trial, Beck told Medscape Medical News, "but certainly there was response in several of the patients, and so we think it's a promising strategy as well."
However, in people with autoimmune disease, she noted, "pembrolizumab could be a really dangerous choice because it might cause exacerbation of that syndrome, so it's certainly not going to be for everyone."
Another possibility is using an agent like pembrolizumab in combination with the donor cells to augment the cell therapy, she said, "and if it would get the patient's cells to activate more, in addition to giving them the boost from the donor cells, that's definitely something we can think about in the future.
"It hasn't been tried to my knowledge, even in the setting of other viral infections, so we don't really know what would happen, and again, we're always concerned about provoking IRIS in the brain, but it's certainly an exciting avenue," Beck added.
The study published on pembrolizumab appeared with two other case studies, one that used pembrolizumab, from researchers in Germany and the United States, led by Sebastian Rauer, MD, University of Freiburg, Germany, and one that used nivolumab, from France with lead author Guillaume Martin-Blondel, MD, PhD, Toulouse University Hospital.
The current work was selected as a top science pick by AAN Science Committee Chair Natalia Rost, MD, MPH, who is also professor of neurology at Harvard Medical School, and a stroke specialist at Brigham and Women's Hospital, Boston, Massachusetts. She called the results "a phenomenal breakthrough."
"As a neurologist myself, giving a diagnosis of PML to a patient is basically giving them a death sentence, and it's one of the most dreaded scenarios in our clinical practice," Rost said.
There has been a surge of PML cases in recent years, she noted, and this is "really tied to the successes of immunotherapies that we've developed over the years, so there is obviously a pendulum of science that swings both directions, so I think this is extremely timely," she said of the current research.
Rost asked Beck whether it might be an option for patients considering starting immunotherapy to bank their own healthy immune cells or even stem cells to have on hand in case PML develops.
Beck said that they had actually considered using autologous cells in this study, but the patients were already on treatment. "Certainly you could consider taking cells before they start on the treatment," she said. "The issue is PML is still a very rare complication of treatment with most of these drugs, so it would be a big resource involved in saving these cells, but certainly a possibility as the technology gets better."
During presentation of these data here during the Contemporary Clinical Issues plenary session, Carolyn B. Britton, MD, associate professor of neurology at Columbia University Irving Medical Center, New York City, was the invited discussant for the paper.
"I was very excited to see that paper," Britton told Medscape Medical News. Adoptive T-cell transfer is not a new approach, having been used successfully for hematopoietic stem cell transplantation, and in some sporadic reports, for PML, she noted.
The current study used a systematic approach, although the patients were very heterogenous, she said. "There are many different paths to the immunosuppression that leads to PML, and so it makes it difficult to do a clinical trial where you can really evaluate the efficacy, but I think they showed very clearly that they had a very safe methodology."
There is still a concern about graft versus host disease, she added, "but so far, it has not materialized."
The researchers made some other early observations that will help refine another more expanded clinical trial to examine efficacy, she noted. But again the heterogeneity of the reasons leading to immunosuppression also mean the paths to immune reconstitution will also be variable, she added.
"But I'm hopeful that this will be something that can help patients early on to stabilize them and to help them improve until one can do a more sustained rescue of the immune system in general," Britton concluded. "So I think it's really a great step forward, and I'm looking forward to their continued work."
The study was supported by the National Institutes of Health Intramural Research Program. Cortese and Beck have reported no relevant financial relationships.
American Academy of Neurology (AAN) 2019 Annual Meeting. Presented May 6, 2019.
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Cite this: Immunotherapy Using Donor Cells Safe in PML - Medscape - May 07, 2019.