T Cells Targeting Epstein-Barr Virus -- A New Treatment for MS?

April 26, 2017

BOSTON — A new approach to the treatment of multiple sclerosis (MS) — use of T cells sensitized to the Epstein-Barr virus — has shown encouraging results in a preliminary study.

The study, presented at the American Academy of Neurology 2017 Annual Meeting (AAN) as part of the Emerging Science Poster Session, was led by Michael Pender, MD, University of Queensland, Brisbane, Australia.

The researchers believe Epstein-Barr virus plays a causative role in the development of MS by infecting B cells and inducing them to attack the brain and spinal cord. By sensitizing a patient's T cells to the virus — an approach known as adoptive immunotherapy — the T cells are enabled to keep the infected B cells under control, resulting in improvements in MS.

In the current study, six patients with progressive MS have so far been treated with autologous Epstein-Barr–specific T cells, and three patients have shown marked benefits, including a large reduction in fatigue and improvements in visual acuity, manual dexterity, lower-limb weakness, and involuntary spasms, the researchers report.

"We are very excited about these results,"  Dr Pender told Medscape Medical News. "If validated in further patients, this would confirm the hypothesis that Epstein-Barr virus and impaired T cell control of Epstein-Barr–infected B cells have a causative role in MS. And it points towards a therapy which would address for the first time the cause of the condition."

Commenting on the study for Medscape Medical News, Jeffrey Cohen, MD, Cleveland Clinic, Ohio, said, "The approach makes sense, and the results are of interest. But beyond that I would be very hesitant to draw strong conclusions from a small open-label uncontrolled study.”

Dr Pender explained that the idea that Epstein-Barr virus was involved in the development of MS was first proposed in 2003. "We suggested that MS was caused by uncontrolled infection of autoreactive B cells by the Epstein-Barr virus, which induced the B cells to make antibodies targeting the brain and spinal cord. Subsequently studies have been published showing increased levels of Epstein-Barr–infected B cells in the brains of patients with MS."

Noting that 90% of the world's population is infected with Epstein-Barr virus but most do not develop MS, Dr Pender suggests that CD8 killer T cells usually keep the infected B cells under control, but patients who develop MS have impaired immune control of these infected B cells. "We believe MS patients have a defect in their T cells, which makes them less effective in controlling these infected B cells."

For the current study, the researchers isolated T cells from patients with MS and grew them in the laboratory with fragments of Epstein-Barr virus in the hope of expanding the number of T cells able to attack B cells infected with the virus. The cells are then readministered to the patients as a course of four dose-escalating injections over a 6-week period. Dr Pender noted that this approach has been used to treat certain malignancies also thought be associated with Epstein-Barr virus.

The first patient with MS — a man with secondary progressive MS — was treated with this approach 3 years ago, and Dr Pender says he has shown "no progression of his disease since receiving the therapy, and some improvement." His case study was published in the Multiple Sclerosis Journal in 2014.

The current study is the next step, and the researchers plan to treat 10 patients — all with primary or secondary progressive MS.

So far they have treated six patients: four with secondary progressive MS and two with primary progressive MS. 

Dr Pender reports that no significant adverse effects have been observed and three patients have shown "symptomatic and objective clinical improvement." 

He notes that before the study, all the patients had very low T cell reactivity to Epstein-Barr — about 0.1%. "This changed to up to 48% after the T cells were multiplied with the Epstein-Barr fragments. Importantly, the patients who have shown the most clinical improvement were the ones whose T cells showed the highest reactivity to Epstein-Barr virus after their incubation."

Dr Pender reports that the main benefit of the treatment appears to be a reduction of fatigue, with the three patients who responded to the treatment all showing significant improvements on the Fatigue Severity Scale.

"One patient with primary progressive MS has shown improvements in visual acuity, color vision, urinary urgency, manual dexterity, and involuntary spasms in the lower limbs. A second patient has shown improvements in balance and productivity," he noted. "A third patient — the one with the most reactive T cells after treatment — has shown the most marked improvement. This patient had lower-limb weakness and spasms for the past 16 years and these have resolved, and walking distance has increased from 100 meters with a walker at baseline to 1200 meters.

"What really drives it home is the benefit we are seeing on the Fatigue Severity Scale," he added. "This scale has a maximum score of 63, and the patient who has shown the most improvement from treatment started with a score of 60. After 6 months this had reduced to 9. I have never seen anything like that in all my years in clinical practice."   

The researchers are planning to continue with the current study to treat all 10 patients by the end of this year. They then hope to continue to larger studies.

"Obviously, we need further larger studies, and we are also investigating how we might be able to increase the response of the T cells in those patients who don't respond initially," Dr Pender said.

He added that it may also be possible to develop HLA-matched T cell products, thereby doing away with the need to use autologous cells.

While they have started with patients who have progressive MS, Dr Pender does not see the therapy being limited to this group. "We tested it in progressive MS patients to begin with as it is more difficult to assess clinical improvements in relapsing-remitting patients in the short term. But I don't see why it wouldn't work in relapsing remitting patients too," he said.

"This is thought of as a controversial approach by some," he added, "but these latest results suggest that it is worth pursuing further and could lead to a completely new treatment strategy for MS." 

The current study was funded by the Multiple Sclerosis Society of Queensland, Multiple Sclerosis Research Australia, and Perpetual Trustee Co Ltd.

American Academy of Neurology 2017 Annual Meeting (AAN). Abstract P4.409 Presented April 26, 2017.

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