Last weekend, I attended the AIMS (Autoimmunity In MS) Charity AHSCT (autologous haemopoietic stem cell transplantation) meeting that was held in Sheffield. All the big guns offering AHSCT to pwMS as a private procedure were there. That was the problem with the meeting; there were no AHSCT naysayers, except my ghost from Christmas past. Applying BBC-like rules to provide both sides of the AHSCT argument would have improved the meeting immensely. Having only YES people at the meeting left me with a slightly bitter aftertaste. Should the aim be to convert the naysayers to your side of the argument?
The scientific messages presented at the meeting haven’t changed, i.e. AHSCT is a highly effective treatment for MS, but it comes with risks, which include a relatively high mortality (0.3%-2%) and a high risk of infertility. What was not discussed openly is the failure rate of AHSCT. Yes, it does not work for everyone. It is pretty clear from published data that many people with MS (pwMS) who have AHSCT still have ongoing smouldering disease, i.e. they still get worse despite having no further relapses and focal MRI activity (NEIDA). In the following graph of Paolo Muraro’s paper (paper 1), you can see that over time, more than 60% of treated patients have worsening of their disability (smouldering MS). It was clear from meeting people at the meeting who had had AHSCT that early treatment when young and not when you have more advanced or progressive MS is the secret to AHSCT success.
It was clear from the meeting that most people in the AHSCT field are still wedded to the dogma that MS is an autoimmune disease and that AHSCT is working by resetting the immune system, by eliminating the cells that cause autoimmunity, or resetting immune regulatory networks, or both.
CAR T-cells - the new kids on the block
You are probably aware that I am convinced that CD19-targeted CAR T-cells will be the next big experiment in MS. I am convinced that CD19-targeted CAR T-cells may cure MS. The latter is based on the truly stunning results of CAR T-cells in systemic lupus erythematosus (SLE) and the fact that these CAR T-cells work well in EBV-associated CNS B-cell lymphomas (please see ‘CAR T-cells as a treatment for MS‘, 17-Sept-2022). The latter tells us these cells traffick to the CNS, kill tumour cells and reduce EBV viral loads.
At the meeting, one talk was dedicated to CAR T-cells in MS and its future promise as an MS treatment (please see ‘Inspiring Change: changing the MS treatment paradigm’ 4-Nov-2023). One international expert, however, dismissed CAR T-cells as a treatment for MS based on the dogma that MS is a T-cell mediated autoimmune disease and that purging B-cells with CAR T-cells would be like using an anti-CD20 therapy and would not stop smouldering MS. What was not mentioned or acknowledged is the fact that anti-CD20 therapies don’t penetrate the CNS to any significant degree (please see ‘Anti-CD20 Kool-Aid’, 11-Sept-2021). In contrast, CAR T-cells will get into the CNS and potentially scrub it clean of B-cells. This is one of the major distinctions between CAR T-cells and anti-CD20 therapies. There is also a large body of evidence in the scientific literature on CNS B-cells and the antibodies they produce as being pathogenic and one of the drivers of smouldering MS. So it makes sense to go beyond peripheral B-cell depletion to target CNS B-cells and their antibody products.
The other big issue that was ignored was the potential causal role of EBV plays in driving MS disease activity (please see ‘More evidence that EBV causes MS’, 6-Sept-2022). If EBV is the driver, CD19-targeted CAR T-cells will purge the body of EBV-infected B-cells, including the CNS and other deep tissue compartments such as the deep cervical lymph nodes. If a specific strain of EBV is causing MS, CD19-targeted CAR T-cells could cure MS by depleting latently EBV-infected B-cells and eliminating the virus from the body. This is why I am so excited about CAR T-cell technology and have spent the best part of 2 years trying to get the pharmaceutical industry to take their CAR T-cell technology into MS. The good news is that a few pharmaceutical companies are progressing with CAR T-cell studies in MS. I hope they will start in the new year. The initial trials will be safety studies and not powered for efficacy. Would you be interested in participating in one of these trials? Or do you consider them too risky?
AHSCT reactivates EBV; is this a problem?
A specific problem discussed at the meeting was the high incidence of EBV reactivation in pwMS treated with AHSCT. In the London cohort (see paper 2 below), 87 out of 109 AHSCT-treated patients had EBV reactivation, with about 70% developing a transient EBV-associated M-protein or paraproteinaemia. The paraproteinaemia is due to a monoclonal expansion of a B-cell that produces high levels of a single antibody (a human monoclonal antibody). I am told that this high level of EBV reactivation, in particular the development of paraproteinaemia, is not seen in patients undergoing AHSCT for other autoimmune diseases and is another indication that pwMS seem to control EBV poorly.
If AHSCT causes EBV reactivation, a driver of MS disease activity, how does it work as a treatment for MS?
PwMS have a problem controlling EBV. A large body of evidence shows that pwMS have increased latent-lytic cycling of EBV. They are more likely to shed EBV in their saliva, have EBV reactivation post-AHSCT, develop lymphoblastoid cell lines when their B-cells are cultured in the laboratory and have higher levels of antibodies and more reactive T-cells to EBV antigens. We also know that pwMS have blunted or exhausted T-cell responses to EBV. The latter is common to a large number of chronic viral infections and is the rationale underpinning the Pender Hypothesis of MS and explains why he developed EBV-reactive cytotoxic T lymphocyte treatments for MS. Sadly, the latter hypothesis has been called into question by the recent negative results of the EMBOLD Atara phase 2 Biotherapeutics ATA188 trial. However, I have made the case that the negative EMBOLD trial results should be ignored in the context of EBV and MS because of bad science (please see: ‘Atara Bio's EMBOLD study is negative’, 9-Nov-2023).
When you study the T-cell repertoire in pwMS, you find it quite restricted. In other words, pwMS have a reduced variety of T-cells in their peripheral blood. This means a fewer number of unique T-cell receptors to respond to foreign proteins or antigens. This reduced or truncated T-cell receptor repertoire is seen with age and is a marker of immunosenescence (ageing immune system). However, when pwMS undergo AHSCT, they widen or rejuvenate their T-cell repertoire. A recent study has shown that this widening T-cell repertoire also occurs in relation to EBV immunity. We hypothesised that AHSCT would do this a few years ago and planned to study this phenomenon in our STAR-MS trial.
What does this mean? I hypothesise that AHSCT is depleting the exhausted anti-EBV T-cells, and when immunosuppressed during the depletion phase of AHSCT, EBV reactivates from its latent to its lytic state, and the result is the production of infective virus. The reconstituting immune system then sees the infective EBV virus and stimulates new T-cell responses to control EBV. Importantly, these new T-cell responses are not exhausted and are very effective at killing and keeping EBV under control. These EBV-reactive T-cells are detected as being different from those present before AHSCT; this is what is meant by ‘diversification and widening’ of the EBV-reactive cytotoxic T-cell repertoire. If this hypothesis is correct, AHSCT acts as an EBV immunotherapy.
I suspect all immune reconstitution therapies (IRTs) in MS are acting as EBV immunotherapies to a greater or lesser extent. If this is correct, we may be able to design much better treatment strategies to treat MS. Rather than using AHSCT as an immunological sledgehammer, we may be able to use a simple therapeutic vaccine to rejuvenate T-cells and widen the EBV-reactive T-cell repertoire. It may interest you that at least one vaccine company is developing a therapeutic EBV vaccine to treat MS. A simpler strategy may be to simply to use EBV antivirals. I am hedging my bets and urging the MS community to try all strategies., including using AHSCT and CAR T-cells to test the EBV hypothesis of MS.
When one delegate at the AIMS meeting in Sheffield told me she had a new immune system after AHSCT, she may have been right, i.e. a new immune system to control EBV.
I know this Newsletter is heavy going with a lot of immunology. Please let me know if you need help understanding what I have written. If not, I will try another tactic.
Paper 1
Importance: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.
Objective: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.
Design, setting, and participants: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.
Exposures: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.
Main outcomes and measures: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.
Results: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
Conclusions and relevance: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
Paper 2
Objective: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.
Methods: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined.
Results: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure.
Conclusions: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.
Classification of evidence: This study is rated Class IV because of the uncontrolled, open-label design.
Paper 3
Both genetic susceptibility and environmental exposures are thought to be involved in multiple sclerosis (MS) pathogenesis. Of all viruses potentially relevant to MS aetiology, Epstein-Barr virus (EBV) is the best-studied. EBV is a B cell lymphotropic virus which is able to evade the immune system by establishing latent infection in memory B cells, and EBV reactivation is restricted by CD8 cytotoxic T cell (CTL) responses in immune competent individuals. Autologous haematopoietic stem cell transplantation (AHSCT) is considered to be the most effective therapy in the treatment of relapsing MS even though chemotherapy-induced lymphopenia can associate with the re-emergence of latent viruses. Despite the increasing interest in EBV and MS pathogenesis the relationship between AHSCT, EBV and viral immunity in people with MS has not been investigated to date. This study analysed immune responses to EBV in a well characterised cohort of 13 individuals with MS by utilising pre-AHSCT, and 6-, 12- and 24-month post AHSCT bio-banked peripheral blood mononuclear cells and plasma samples. It is demonstrated that the infused stem cell product contains latently EBV-infected memory B cells, and that EBV viremia occurs in the immune-compromised recipient post-transplant. High throughput TCR analysis detected expansion and diversification of the CD8 CTL responses reactive with EBV lytic and latent antigens from 6 to 24 months following AHSCT. Increased levels of latent EBV infection found within the B cell pool following treatment, as measured by EBV genomic detection, did not associate with disease relapse. This is the first study of EBV immunity following application of AHSCT in the treatment of MS and not only raises important questions about the role of EBV infection in MS pathogenesis, but is of clinical importance given the expanding clinical trials of adoptive EBV-specific CTLs in MS.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
AHSCT vs. CAR T-cells to treat MS