Multiple Sclerosis Society of Canada

Latest MS Research News

Landmark MS Scientific Research Foundation funded study demonstrates that “rebooting” the immune system stops new disease and leads to recovery in people with aggressive multiple sclerosis

  • Canadian Study
  • MS Society Funded
Background

Currently, disease-modifying therapies (DMTs) approved for multiple sclerosis (MS) appear to work by blunting the destructive autoimmune response that targets tissues in the central nervous system (CNS). For many individuals living with MS, DMTs offer measurable therapeutic benefits by suppressing MS relapses and, in some cases, delaying the accumulation of disability. However, for aggressive forms of MS, autoimmune attacks can be unrelenting and relapses and disability can persist despite treatment with conventional therapies. This has raised the question: what if we could press the “reset” button, effectively erasing the disease-causing immune system and re-building a healthy one that can fight infection and not cause harm to the CNS?

To explore this question, the MS Society of Canada and its affiliated Multiple Sclerosis Scientific Research Foundation (MSSRF) funded a multi-centre clinical trial in 2000 led by Drs. Mark Freedman and Harry Atkins at the Ottawa Hospital Research Institute to study the potential of eliminating the faulty immune system, and reconstructing a healthy one that is tolerant towards its own tissues in people living with MS. This procedure – referred to as immunoablation and autologous hematopoietic stem cell transplantation (IAHSCT) – is commonly used to treat individuals with certain types of blood cancer like lymphoma.

The Canadian Bone Marrow Transplantation (BMT) trial involved harvesting hematopoietic stem cells (stem cells that give rise to the blood) from the bone marrow of the participants, administering a strong dose of chemotherapy to destroy their abnormal immune systems, and then reintroducing the harvested stem cells to the participants to grow a new immune system. Follow-up was done over an extended period of time to determine whether the procedure would lead to long-lasting, beneficial effects.

Results of the Canadian BMT Trial, published this week in renowned medical journal The Lancet, found that rebooting the immune system with IAHSCT stopped brain inflammation in participants who completed the treatment, and in some cases led to substantial, long-term recovery of certain MS-related disabilities.

The Study

The trial was a multi-centre, single-arm (non-randomized), phase II clinical trial that involved 24 individuals who presented with highly inflammatory MS, meaning they experienced frequent relapses and did not respond to DMTs. Participants also showed early signs of rapid development of sustained disability. For the stem cell harvesting procedure, hematopoietic stem cells were triggered to enter into the blood circulation from the bone marrow, then collected and stored. The researchers ensured that only immature stem cells that were not hardwired to target myelin were included in the final sample.

Participants were treated with potent chemotherapy to eliminate the immune system under careful medical supervision. Two days after chemotherapy, each participant received an infusion of their own stem cells (a procedure referred to as an autologous transplant) to permit the production of new immune cells in the bone marrow.

Participants were monitored over a period ranging from 4 to 13 years post-treatment, and disease activity before and after the procedure was compared. During the follow-up period, the researchers assessed changes in disability using the Expanded Disability Status Score (EDSS). They also measured the number and size of inflammatory brain lesions as well as overall changes in brain volume over time using magnetic resonance imaging (MRI). Each participant was also monitored for any adverse events. The primary endpoint (the main outcome that the researchers looked for and measured) was established to be MS activity-free status (the absence of relapses, brain lesions or disability progression) over 3 years.

Results

The IAHSCT procedure resulted in complete elimination of clinical disease activity (specifically, no new relapses were observed) in 23 participants during the entire follow-up period, which was a dramatic improvement compared to disease activity before the procedure. Similarly, no new brain lesions were detected on MRI for all participants. Although the rate of brain volume loss initially increased for the first 6 months after the procedure, the rate of loss then slowed and stabilized in all participants.

The researchers also found that 70% of participants showed no evidence of disability progression over long-term follow-up. Additionally, approximately 40% of participants experienced unexpected improvements in disability, such as recovered strength and improved movement coordination. Finally, some participants experienced marked improvements in several measures of social wellbeing; for instance, 37% of participants who were on disability insurance no longer required coverage and were able to return to work or school, while 31% married or became engaged, and one gave birth to a child.

One participant died of complications from liver failure approximately 2 months after undergoing the IAHSCT procedure – since the participant underwent the full procedure, they were included in the final analysis. Another participant required intensive care resulting from chemotherapy-related toxicity, but ultimately recovered. Some participants also experienced anticipated post-transplant viral infections and subsequently recovered.

Comment

The use of IAHSCT as a therapeutic approach to treating aggressive, highly inflammatory MS was a relatively new concept when Drs. Freedman and Atkins applied for MSSRF funding in 2000. Years later, this work has paved the way for further research into IAHSCT around the world. The HALT-MS trial, for example, reported that 78% of participants showed no new disease activity over 3 years following a similar procedure. The Canadian BMT Trial is the first study to show no new inflammatory disease activity in all of the participants who completed the procedure for up 13 years post-treatment, as well as the unexpected finding that disability progression ceased and long-term functional recovery was seen in a significant proportion of participants. The researchers distinguish the Canadian BMT Trial from other trials in that it involved a higher chemotherapy dose that completely eliminated the immune system, which they believed allowed for robust, long-term benefits.

Additional experiments that followed the trial have helped to explain, at the cellular level, why participants experienced notable improvements. These include an immunological study published by Dr. Amit Bar-Or (Montreal Neurological Institute), which found that the absence of Th17 cells in the newly established immune system of the IAHSCT-treated participants linked that specific T cell subtype to the autoimmune response in MS. Additionally, an imaging study published by Dr. Douglas Arnold (Montreal Neurological Institute) assessed demyelination and remyelination in participants enrolled in the trial. This follow up work provided a window into the mechanisms underlying the success of the procedure.

Findings from the trial also address important questions regarding the origin of MS. The discovery that destroying the disease-causing immune system and rebuilding a new, healthy one leads to long-lasting absence of new disease lends strong support to the hypothesis that MS is driven by the abnormal immune system, rather than the abnormal immune response being a secondary reaction or MS being purely driven by genes.

While findings from this study are extremely encouraging, the authors caution that the procedure carries significant risk due to the use of strong chemotherapy. The procedure is thus intended for people living with highly inflammatory, relapsing forms of MS who do not benefit from other immune-modifying therapies. It’s unclear whether it can serve as a treatment for those who have experienced a high level of MS-related disability over prolonged periods of time and/or exhibit low levels of inflammation in the central nervous system. Nonetheless, these published results greatly contribute to the understanding of IAHSCT for a specific group of individuals with MS.

Source

Atkins HL et al. (2016) Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. The Lancet. [Epub ahead of print]