The Epstein-Barr virus, which causes glandular fever, is a long-time suspected MS trigger. Ian Cook investigates its involvement in immunotherapy treatment that is now being developed as a possible treatment
One of the many theories about the cause of multiple sclerosis (MS) is that a virus is involved, and over the years several viruses have been investigated. Interestingly, the main suspect viruses are different members of the same family of virus – the herpes family.
The particular herpes virus that has attracted most interest is, of course, the Epstein-Barr virus (EBV) and the reason is obvious when you look at the statistics. A recent German study found EBV infection was present in 100 per cent of the 901 MS patients that took part.
This 100 per cent correlation is a fairly striking fact and it is disappointing that there has until recently been little headway in proving the seemingly obvious theory that EBV is actually one of the causes of MS. All this may be about to change, however, and this is due largely to the work of Michael Pender, a consultant neurologist at the Royal Brisbane and Women’s Hospital and Professor of Medicine at The University of Queensland.
Professor Pender believes that a large body of evidence shows that infection with Epstein-Barr virus (EBV), which causes glandular fever, also known as infectious mononucleosis, has a role to play in the development of MS several years after the original EBV infection. One of the reasons is that after infection the virus lives on in B cells, the white blood cells that make antibodies. Once a person is infected with EBV, they carry the virus in these B cells for the rest of their life.
Professor Pender believes that in MS, infection with EBV leads to the creation of ‘autoreactive’ B cells, which accumulate in the brain. Once there, these autoreactive cells produce anti-brain antibodies which ultimately lead to the destruction of myelin in the brain and other parts of the central nervous system.
By living on after the initial infection, EBV is behaving in a similar way to other members of the herpes family of viruses. This is something you may know from personal experience. After infection with herpes simplex virus (cold sores or Human Herpes Virus 1 (HHV 1)) the herpes virus hides inside nerve cells, hibernating there for life, and periodically waking up from its sleep to reignite infection, causing the cold sores to recur. If you have ever had chickenpox (HHV3) you will also know this can later recur as shingles, the virus also going into dormancy hiding again in nerve cells until returning years later in nerves that lead to the skin.
Professor Pender’s theory about EBV (HHV4) has made several predictions which have subsequently been verified by studies he has conducted, including the presence of EBV-infected B cells in the brain in MS. Perhaps most importantly, over the past few years, working with other researchers, Professor Pender has gone on to use an immunotherapy which involves growing immune cells from the blood of MS patients with fragments of EBV proteins to retrain killer CD8 T-cells (another type of white blood cell) to be potent killers of EBV-infected B cells. The retrained killer CD8 T-cells are then administered to the patient by intravenous infusion. This treatment, known as ‘autologous EBV-specific T-cell therapy’, does not require the use of any drugs.
A Phase 1 clinical trial tested the safety and tolerability of this therapy in patients with primary and secondary progressive MS. The results of the study were recently published in the journal JCI Insight. Of the 13 recruited participants, 10 received the full course of T-cell therapy. The majority showed improvement, with six experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, and improved quality of life. All six patients receiving T-cells with strong EBV reactivity showed clinical improvement, whereas only one of the four patients receiving T-cells with weak EBV reactivity showed improvement. There were no serious side effects associated with the treatment.
Most recently, and following on from Professor Pender’s work, a US bio-technology company, Atara Biotherapeutics, has developed an experimental therapy called ATA 188 to treat both progressive and relapsing-remitting MS in this way. ATA188 is an EBV-specific T-cell product derived from healthy people. This therapy is known as allogeneic EBV-specific T-cell therapy and differs from autologous EBV-specific T-cell therapy in that T-cells are derived from healthy subjects (allogenic) rather the MS patients themselves (autologous).
A Phase 1 clinical trial is currently recruiting patients (in the US and Australia) with relapsing-remitting MS and progressive MS to test the safety and tolerability of ATA188 as well as find the best dose for a Phase 2 clinical trial. The trial aims to recruit patients who will receive intravenous infusions of ATA188 at treatment centres in the USA and Australia. The study completion date is 2026.
Five years may seem a long way away for news about a revolutionary new treatment for MS. However, in an illness that was first identified more than 140 years ago, most MSers would agree that nothing happens quickly and sadly we will just have to wait and see. Hopefully, the wait will be worth it.