Professor Michael Pender explains how anti-EBV cell therapy works in MS. #MSBlog #MSResearch
"At the request of one of you and following on from his recent publication on treating EBV by transfer of virus killing T cells we asked Prof. Michael Pender from Australia to give you more details on his group's work."
Professor Michael Pender graduated from The
University of Queensland in 1974 with First Class Honours in Medicine and a
University Medal. Over the next six years he trained as a physician and
neurologist at the Royal Prince Alfred Hospital and St Vincent's Hospital,
Sydney, and became a Fellow of the Royal Australasian College of Physicians in
1981. During his clinical training he developed a keen interest in multiple
sclerosis which has continued since then.
After completing clinical training in
neurology, he commenced research on experimental autoimmune encephalomyelitis
under the supervision of Professor Tom Sears at the Institute of Neurology,
Queen Square, London. In 1983 he was awarded a PhD from the University of
London and Queen Square Prize for Research. From 1984-1986 he continued this
research as a Research Fellow at the John Curtin School of Medical Research,
Australian National University, Canberra, in the Department of Experimental
Pathology chaired by Professor Peter Doherty, Nobel laureate. In 1987 he was
appointed Senior Lecturer in the Department of Medicine, The University of
Queensland, at the Royal Brisbane Hospital. In 1989 he was awarded a Doctorate
of Medicine from The University of Queensland for research on experimental autoimmune
encephalomyelitis and was promoted to Reader in Medicine. In 1995 he was
promoted to Professor of Medicine (Personal Chair), The University of
Queensland. He also held the position of Director of Neurology, Royal Brisbane
and Women's Hospital, from 1992-2005. He is Director of The University of
Queensland Multiple Sclerosis Research Centre and an Honorary Senior Principal
Research Fellow at the QIMR Berghofer Medical Research Institute, and directs the
Multiple Sclerosis Clinic at the Royal Brisbane and Women's Hospital. In 2006
he was awarded the Multiple Sclerosis Australia Prize for Multiple Sclerosis
Research - 'For outstanding commitment and dedication to research into the
cause and cure of Multiple Sclerosis in Australia'. In 2011 he received the
John H Tyrer Prize in Internal Medicine, The University of Queensland, for
research in the field of Internal Medicine.
Professor Pender writes:
A large
body of evidence indicates that infection with Epstein-Barr virus (EBV) has a
role in the development of multiple sclerosis (MS). EBV infects B cells and
plasma cells, the white blood cells that make antibodies. Once a person is
infected with EBV, they carry the virus in their B cells for the rest of their
life. Normally the number of EBV-infected B cells is kept under tight control
by the immune system especially by CD8+ T cells, which kill the infected
cells.
In 2003 I published a new theory in Trends
in Immunology proposing that chronic autoimmune diseases such as MS and
rheumatoid arthritis are caused by uncontrolled EBV infection leading to
infection of autoreactive B cells, which accumulate in the organ affected by
the autoimmune disease. I proposed that MS was caused by the accumulation in the
brain of EBV-infected autoreactive B cells which produce anti-brain antibodies
and also provide survival signals to autoreactive T cells that would otherwise die
in the brain by apoptosis (programmed cell death). The theory made predictions
which have subsequently been verified, namely: the presence of EBV-infected B
cells in the brain in MS; a beneficial effect of rituximab which kills B cells,
including EBV-infected B cells; decreased CD8+ T cell immunity to
EBV in MS; and EBV infection of autoreactive plasma cells in the joints of
people with rheumatoid arthritis. It also predicted that boosting CD8+
T cell control of EBV by vaccination or by adoptive immunotherapy would prevent
and successfully treat chronic autoimmune diseases.
EBV-specific
adoptive immunotherapy involves growing T
cells from the blood in the laboratory with an EBV vaccine to retrain the cells
to be potent killers and then returning them to the patient by intravenous
infusion. This treatment was developed by Professor Rajiv Khanna of the QIMR
Berghofer Medical Research Institute in Brisbane to treat patients with
EBV-related malignancy and does not require the use of any drugs. Professor
Khanna and his team have successfully used this therapy to treat EBV-related
metastatic nasopharyngeal carcinoma. This EBV vaccine expresses parts of three
EBV proteins, which are crucial in allowing EBV-infected B cells to multiply
and mature into memory B cells and plasma cells capable of producing large
amounts of antibody. As it happens, Francesca Aloisi’s group have shown that
these same three EBV proteins are the main EBV proteins present in the
brain-infiltrating EBV-infected B cells in MS.
EBV-specific adoptive immunotherapy has
not previously been used to treat people with MS or any other autoimmune
disease. Because we were concerned that the therapy might aggravate
inflammation in the brain and actually worsen MS, we reduced the initial dose
of T cells to 25% of the dose used by Professor Khanna to treat EBV-related
malignancy. We then gradually increased the dose over the next three infusions,
which were administered at fortnightly intervals. The first recipient was a 42
year old man with secondary progressive MS. The treatment had no adverse
effects and within 2 weeks the patient began to experience clinical improvement.
This was followed by further improvement, with a reduction in fatigue and
painful lower limb spasms, an improvement in cognition and hand function, and increased
productivity at work. These improvements were sustained up to the time of the
latest review, 21 weeks after the final T cell infusion, when neurological
examination demonstrated increased movement of his legs. There was also reduced
disease activity on his MRI brain scan and reduced antibodies in the
cerebrospinal fluid.
We believe that the beneficial effects
of the therapy are due to the killing of EBV-infected B cells in the brain by the
transferred CD8+ T cells. The beneficial effect of boosting immunity
to EBV by this treatment highlights the importance of impaired immunity to EBV
in the development of MS. A clinical trial is now needed to determine safety
and therapeutic efficacy across the clinical spectrum of MS.
CoI: None