Background to our clinical work

The primary objective of the Multiple Sclerosis Research Group is to discover new insights into the cause of multiple sclerosis by conducting immunological, virological, biochemical, clinical and genetic research, with the ultimate goal of preventing and curing the disease. In particular, our research focuses on: (1) the role of autoreactive T cells and autoantibodies in mediating immune attack on the brain; and (2) the role of Epstein-Barr virus in initiating and sustaining this attack.

The aim of our clinical research is to explore whether a novel treatment targeting Epstein–Barr virus (EBV) is safe and effective in people living with progressive forms of MS.

What is EBV and why are we targeting it?

EBV is the virus that causes glandular fever. It infects cells of the immune system and persists in those cells for the lifetime of the infected person, even when they feel well. Infection with EBV is an important risk factor for developing MS. In 2003 Professor Pender proposed the theory that EBV-infected cells accumulate in the central nervous system and lead to the development of MS in susceptible people. Since then, increasing evidence has supported this theory and indicates a crucial role for EBV in the development of MS.

How does the novel treatment work and what experience do we have so far?

The treatment is called ‘adoptive T cell immunotherapy’. It aims to boost the immune response to EBV. White blood cells known as T cells, which kill virally infected cells, are exposed to fragments of EBV in a laboratory to boost the number of T cells capable of recognizing and killing cells infected with EBV. Adoptive T cell immunotherapy using the patient’s own T cells was shown to be safe in Professor Pender’s previous phase 1 trial of 10 patients with primary or secondary progressive MS. The current research builds on this experience by employing another form of T cell immunotherapy which uses T cells from healthy donors. Our site is the lead Australian site.

What is the timeline of the research?

This research has been developing over decades. Below is a timeline to indicate the major milestones that led to the clinical trial of EBV-specific T cell therapy for MS:

2003: Professor Pender publishes his landmark hypothesis that EBV infection of autoreactive B lymphocytes leads to chronic autoimmune diseases, including MS (1)

2007: A prediction of the hypothesis is confirmed:  EBV-infected B cells and plasma cells are found in the brain in MS (2)

2008: A second prediction of the hypothesis is confirmed: A beneficial response to B-cell depletion was found in MS (3)

2009: A third prediction of the hypothesis is confirmed: Decreased CD8+ T-cell immunity to EBV-infected B cells are found in MS (4)

2012: Professor Pender expands on his landmark theory publishing a unifying hypothesis for autoimmunity: “CD8+ T-Cell Deficiency, EBV  Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis” (5)

2013: A key prediction of the hypothesis is confirmed: autoreactive plasma cells in the joints of people with rheumatoid arthritis are found to be infected with EBV (6)

2014: A key prediction of the hypothesis is again confirmed: autoreactive plasma cells in the salivary glands of people with Sjögren’s syndrome are found to be infected with EBV. (7)

2014: A further prediction of the hypothesis is confirmed: Deficiency of effector memory CD8+ T cells is found to be an early and persistent feature of MS and might underlie the impaired CD8+ T cell control of EBV infection. (8)

2014: In a world first, Professor Pender and his research team treat an MS patient with EBV-specific adoptive immunotherapy. The treatment was safe and the patient showed clinical improvement with reduced disease activity indicated on MRI brain scan and in spinal fluid. (9)

2016:  In a world first clinical trial, Professor Pender leads a phase I trial of autologous EBV-specific T cell therapy. 10 patients with progressive forms of MS are treated. There are no serious adverse events and 7 patients show an improvement. (10)

2017: Defective T-cell control of EBV infection is once again confirmed in MS. (11)

2017: A larger international clinical trial of allogeneic EBV-specific T cell therapy known as ‘ATA188’ begins. The UQ/RBWH site is the lead Australian site with two other Australian sites working under its ethics banner.

2019: Professor Pender presents the preliminary results of the ATA188 trial at the ‘European Academy of Neurology’ conference in Oslo, June 29th to July 2nd 2019. Results are also presented in poster form at ‘European Committee for Treatment and Research in MS’ in Stockholm, September 2019.

2020: The fourth amendment of the ATA188 clinical trial receives ethical approval and is launched at the UQ/RBWH site. This enables patients who are already enrolled in the trial to receive further treatment. It also allows new patients to be enrolled into a randomized, double-blind, placebo-controlled part of the study. This trial is expected to remain active until 2025.

How long does it take for an experimental treatment to reach the drug market?

After a phase I trial which aims to determine how safe a treatment is, the next step is a phase II trial. Generally, phase II trials explore the new intervention’s effectiveness in patients with a disease over a few years.  If the new intervention is thought to be safe and effective the next step is a larger phase III trial comparing the intervention to a placebo. Following this, a new drug application can be made to the drug regulatory body. In Australia this is the Therapeutic Goods Administration (TGA). It can take many years for an intervention to undergo clinical studies, be granted approval by regulatory bodies and to reach the market for patient access.

References

  1. Pender MP. Infection of autoreactive B lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003;24(11):584-8.
  2. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204(12):2899-912.
  3. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-88.
  4. Pender MP, Csurhes PA, Lenarczyk A, Pfluger CM, Burrows SR. Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry. 2009;80(5):498-505.
  5. Pender MP. CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis. Autoimmune diseases. 2012;2012:189096.
  6. Croia C, Serafini B, Bombardieri M, Kelly S, Humby F, Severa M, et al. Epstein-Barr virus persistence and infection of autoreactive plasma cells in synovial lymphoid structures in rheumatoid arthritis. Ann Rheum Dis. 2013;72(9):1559-68.
  7. Croia C, Astorri E, Murray-Brown W, Willis A, Brokstad KA, Sutcliffe N, et al. Implication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjogren's syndrome. Arthritis Rheumatol. 2014;66(9):2545-57.
  8. Pender MP, Csurhes PA, Pfluger CM, Burrows SR. Deficiency of CD8+ effector memory T cells is an early and persistent feature of multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2014;20(14):1825-32.
  9. Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, et al. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2014;20(11):1541-4.
  10. Pender MP, Csurhes PA, Smith C, Douglas NL, Neller MA, Matthews KK, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI insight. 2018;3(22).
  11. Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clinical & translational immunology. 2017;6(1):e126.