Pathways to Cures

Barts-MS rose-tinted-odometer ★★★★★ 

I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me. 

As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people. 

Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences. 

So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me! 

If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease? 

Sonia Vallabh. The Patient-Scientist’s Mandate. N Engl J Med 2020; 382:107-109.

Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.

There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease. 

My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS. 

Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with. 

In the area of MS prevention, it will take more than a  patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.

My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?

Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there. 

On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.

For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold. 

I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.

A smoking gun?

The big hole in the EBV hypothesis of MS is how does the virus cause the disease at a molecular and immunological level. There are as many theories as thinkers. 

One theory is that EBV infects the CNS and MS is caused by an immune response to the virus in the brain of MSers. MS is then due to bystander damage of the immune cells finding and attacking the EBV infected cells. The evidence that EBV infects the brain is strengthening but is not an accepted fact.  In fact, it remains very controversial.

In the paper below from Francesca Aloisi’s laboratory, it shows that a large number of CD8 T-cells in the brains of MSers are EBV-specific targeting EBV proteins from both the latent and lytic phase of the EBV life-cycle. This is potentially a very important paper but needs to be reproduced. 

The big hole in the EBV-infected brain and CD8+ T-cell hypothesis is why do patients do so well on natalizumab and why does anti-CD20 therapy prevent rebound post-natalizumab? 

If the brain was infected with EBV and you blocked immune surveillance using natalizumab surely you could expect some ill-effects? We don’t see this happening clinically. In fact, we see the opposite; MSers on natalizumab have NEDA, a lot of them see an improvement in disability, they ‘normalise’ brain volume loss, they see a reversal of fatigue and/or sickness behaviour, etc. Surely natalizumab is the one experiment that argues against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may not stop smouldering MS which is the true disease and this may take many decades to manifest itself.

If MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of MSers, why does rituximab a drug that takes out predominantly B-cells and not CD8+ cells prevent rebound post-natalizumab? Some have argued that the B-cells are needed to travel to the brain to present antigen to the CD8+ T-cells. I don’t by this there are other professional antigen-presenting cells in the brains of MSers that can do this job. Others quote the new evidence that T-cells need help from B-cells to cross the blood-brain barrier. This does not explain why some of the carry-over PML cases from natalizumab to rituximab (or ocrelizumab) have developed IRIS (immune reconstitution inflammatory syndrome).  In the latter cases IRIS causing T-cells are trafficking to the brain in the absence of circulating B-cells.

So this paper generates more questions than it answers. It does demonstrate that we need to really find-out if EBV is driving MS from within the CNS or from its effects on the immune system in the periphery. These two scenarios require different treatment approaches. However, this should not stop us from exploring both approaches, often it is the experiment that disproves the hypothesis.

It looks as if October 2019 is going to be the month of EBV and MS. 

Serafini et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus-infected cells: a clue for a virus-driven immunopathological mechanism. J Virol 2019 (accepted manuscript) DOI: 10.1128/JVI.00980-19

ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.

Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.

Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.

IMPORTANCE: EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

CoI: multiple

The cause of MS

When I posted the link to our EBV and MS meta-analysis on social media yesterday I was taken to task because of the slow progress we have made in MS prevention.

Can I remind you that science moves steadily and slowly and the biggest problem we have is the slow adoption, or rejection, of innovations or new ideas. 

“The human mind treats a new idea the same way the body treats a strange protein; it rejects it.”
Peter Medawar, Nobel prize laureate, in Physiology or Medicine, 1960.

I was convinced by the evidence already back in 1999 that EBV was the likely cause of MS. I have been working on EBV ever since and the progress has been very slow. The main reason I left the Institute of Neurology (Queen Square) was to move to a multi-disciplinary institute, that would allow me space and time to work on EBV. However, it takes more than just moving to a new research environment to build momentum around a new research hypothesis. 

I have had more grant applications rejected around the viral hypothesis of MS than I care to count. It is very depressing. Despite this, we are pushing on slowly with our plans to create a trial-ready cohort of people at high risk of MS for exploratory MS prevention studies. Dr Ruth Dobson is doing quite an amazing job at getting this off the ground. We are also pushing forward with our ideas around treating MS with antivirals that target EBV. To say that the funding for doing these trials has been difficult is an understatement, but I am hoping if we can get pilot data we can convince the sceptics to fund definitive trials. 

We are also not the only team working on the EBV hypothesis of MS. Michael Pender in Brisbane, Australia, is doing great things and Atara Bio has taken up the baton in industry. I have recently posted on their preliminary results that were presented at ECTRIMS.

I spend most of my waking day doing MS and a large part of that is thinking about EBV and MS prevention. The main strand of MS prevention is an EBV vaccination study. The vaccine is not in our hands, but the capable hands of Jeff Cohen at the NIH, and hopefully a deep-pocketed Pharma company to commercialise it. Even if we get an effective EBV vaccine developed and launched we will still have to overcome the public resistance to vaccination and to convince public health officials that this is a worthy idea. 

The battles ahead are numerous, but we will get there in the end. We have to. We don’t want the next generation of MSers asking us why we haven’t done anything to prevent MS given the current state of knowledge.

EBV is almost certainly the cause of MS. What are we doing about it?  

Jacobs et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors.

Background: EBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. 

Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. 

Methods: Pubmed was searched using the terms multiple sclerosis AND Epstein Barr virus, multiple sclerosis AND EBV, clinically isolated syndrome AND Epstein Barr virus and clinically isolated syndrome AND EBV. All abstracts were reviewed for possible inclusion. 

Results: 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10-4; RERI 3.84, p<5×10-3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. 

Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

CoI: multiple

Black Swan

Most of you know by now that I am one of the main proponents supporting EBV as the primary cause of MS. I think EBV is actively driving MS disease activity. The corollary to this statement is that we may be able to treat MS with anti-EBV drugs. We have suggested that all MS DMTs work by affecting memory B-cell biology and that this is the cell that host the EB virus. At Barts-MS, we have an active research programme to test anti-EBV drugs in MS.

One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive. Almost too good to be true! Most of the MS community has dismissed his data as being biased due to being unblinded and from one centre. However, if you drill down into his data you will see that most of the MSers he has treated have had quite advanced disease with high EDSS scores and the improvements in disability have been so profound that it would be difficult to ascribe this to biased EDSS-rating. I am convinced that Michael Pender is onto something big and something very important.

This is why the ATARA Bio early phase 1b data is my one of my #ECTRIMS2019 highlights. Instead, of autologous cells, ATARA Bio is using MHC-matched allogenic CTLs. The good news from their poster presentation is that these cells seem safe as a treatment and at the high doses they are reproducing Pender’s single-centre results.

I agree it is too early to be jumping up and down and that we need to wait for the results of a randomised double-blind controlled study, but imagine a world in which we treat MS with anti-EBV CTLs and our MSers notice profound improvements in disability? This would be a true paradigm shift, a black swan event! Overnight MS would be classified as an infectious disease. Could you imagine what would happen to the MS DMT market? I sincerely hope for the MS community that this remarkable story pans out to be true.

Prof G’s ECTRIMS Highlight #2

Pender et al. Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis. ECTRIMS 2019 Abstract: P1657.

Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).

Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.

Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188. 1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.

Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.

Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).

Pender et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018 Nov 15;3(22). pii: 124714. doi: 10.1172/jci.insight.124714.

BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).

CONCLUSION: EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527.

FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.

CoI: multiple

To B or not to B

Is targeting the B-cell sufficient to get on top of MS or do we need something extra?

I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.

It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.

A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.

The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.

Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).

I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.

So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.

You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.

My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.