black swan

EBV: is it time to pluck the black swan?

Barts-MS rose-tinted-odometer: ★★★★★
London Gray & Raining #666677 #C4D3DF

SEPSEPIEN a commentator this morning said: “Would have been more rewarding to find a DMT that successfully addresses the causes of MS”. I agree and I really think we have found the cause of MS. It is Epstein Bar Virus (EBV). The epidemiology is pretty convincing that EBV acts in the MS causal pathway and all of our effective i.e. licensed DMTs work on memory B-cell where the latent EBV virus resides.

The piece on my #1 ECTRIMS-2021 highlight, i.e. the MRI changes in relation to treatment with Atara Bio’s anti-EBNA1 allogeneic CTLs (cytotoxic T-cells), has resulted in at least ten emails from business analysts wanting to speak to me about the product. I think it is my reference to a ‘Black Swan’ that piqued their interest. What they don’t realise is that when you pluck a black swan it looks just like a plucked white swan.

So if Atara Bio gets their product to market they will get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents. What do I mean?

Rituximab (anti-CD20) is licensed to treat EBV-associated lymphoproliferative disorders. Peripheral EBV viral loads plummet when you administer anti-CD20 therapies. In other words, anti-CD20 therapies are anti-EBV drugs so why would you need to use an expensive cellular therapy? To get into the CNS. Step up the CNS penetrant BTK inhibitors.

Ibrutinib the first licensed BTKi is a potent anti-EBV drug and works very well against EBV-associated lymphomas including CNS lymphomas. EBV in fact uses BTK as a signalling molecule to bypass B-cell receptor-mediated cell cervical signals.

MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery with the exception of natalizumab that blocks trafficking of memory B-cells into the CNS.

So all it will take for Big Pharma to pluck Atara Bios black swan is for them to produce data showing how their DMTs impact EBV viral infection in the periphery and potentially in the CNS. The frustrating thing for me is I have been trying to get Pharma to do these studies for decades. Just maybe with a black swan soaring up above they may start to listen. I suspect some of the companies have data on this already.

The good thing that Atara Bio has done is to move EBV centre stage. So maybe now we will get some momentum behind our EBV vaccination study off the ground.

For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study. It is almost too good to be true, which is why I referred to it as the Lazarus effect.

Plucked Swan | monsieurpolk — A plucked swan; was it a black or white swan?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50.

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

#BlackSwan: anecdotal evidence we can’t ignore

Barts-MS rose-tinted-odometer: ★★★★★

What is a black swan event?

“The black swan theory or theory of black swan events is a metaphor that describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalised after the fact with the benefit of hindsight”. (Source Wikipedia)

The case study below is another example of a mounting number of case studies of patients with MS being treated with antivirals, with activity against EBV, doing well. We now need to do properly powered randomised controlled trials to test the EBV causation of MS hypothesis definitively.

Prof. Julian Gold and I launched the Charcot Project in 2012 to investigate the viral aeitology of MS. We tried on numerous occasions to get trials funded to test this hypothesis and have failed. We managed to test one anti-retroviral in a small proof-of-concept study, which was negative. Since then we have managed to get funding to see if famciclovir is capable of suppressing EBV shedding in the saliva. This study should have been completed by now, but we had to delay its start because of the COVID-19 pandemic.

We have also managed to show that teriflunomide is anti-EBV in that it reduces EBV viral shedding in the saliva of people with MS. I suspect this is a very relevant an important observation and underpins the iTeri study, i.e. to use a B-cell depleting agent as induction therapy and teriflunomide or related compound as a maintenance therapy to prevent EBV reinfecting B-cells during the B-cell reconstitution phase.

Life is short and I started working on EBV as a cause of MS way back in 2005 and feel like I am treading water. The evidence that EBV is the cause of MS is so overwhelming that we really can’t afford to ignore it any longer. What we need is a substantial investment from the major funding agencies, MS charities, wealthy philanthropists and Pharmaceutical companies with antiviral drugs in their portfolio to prove (or disprove) that EBV is the cause of MS.

When you apply Bradford-Hill’s causation theory to EBV being the cause of MS there is only one criterion out of nine that still needs to be ticked and that is experimental evidence. What we need are therapeutic interventional trials targeting EBV to complete the proof.

Torkildsen et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord 2020 Oct 7;46:102569. doi: 10.1016/j.msard.2020.102569.

Some antiretroviral medications are also inhibitors of EBV. We describe a patient with highly active MS who was infected with HIV and started HIV-treatment containing tenofovir alafenamide (TAF), a potent inhibitor of EBV lytic reactivation. Her MS was in complete remission during this treatment, and she had new radiological disease activity again after switching to tenofovir disoproxil fumarate, an HIV drug with less potent activity against EBV replication. Based on the recently detected mechanism of TDF and TAF, we suggest that further studies on these drugs in MS are warranted.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19 transient antibody responses

The MS community is panicking because a handful of pwMS on anti-CD20 therapy don’t seem to make antibody responses to SARS-CoV-2. The implications are that these patients are susceptible to reinfection. We can’t be sure of this as lasting long-term antiviral immunity may rely more on T-cell responses, in particular CD8+-T-cell responses, than antibody responses. Let’s hope this is the case.

The study below done in London shows that even in people from the general population with confirmed virus-positive COVID-19 rapidly lose their neutralizing antibody response to the virus. Are we surprised? No this is well described with both SARS-CoV-1, SARS-CoV-2 and other coronaviruses.

What does this mean for the pandemic? It means that vaccine responses may need to be tracked with other immunological techniques outside of easy-to-develop and easy-to-do standard antibody assays. In short, we may not be able to rely on anti-SARS-CoV-2 antibodies to assess the effectiveness of a vaccine.

The monitoring of T-cell responses to viruses and other organisms is not trivial when you need to do it at scale. We will need to develop so-called T-cell proliferative-type response assay at speed. What this means is that we need to be able to measure if T-cells response to coronavirus antigens by dividing or activating themselves and producing cytokines. The latter is the easiest test to scale-up and is the method that is currently used in the Quantferon assay for latent or active TB.

The challenges posed by SARS-CoV-2 for the world community is quite extraordinary and one has to wonder why coronavirus research funding was not continued and ramped-up after the SARS-CoV-1 epidemic in 2002-2003. Black swan events can be predicted; it is all about odds. I was pleasantly surprised to read the World Bank in 2017 had set the risk of a coronavirus pandemic in the next decade at 5.9%. They thought that the odds of a coronavirus pandemic was more than a 1 in 20 and this is only one of the risks that underpinned their catastrophic pandemic bonds issue; i.e. an insurance policy for low-income countries to deal with a catastrophic event. If the World Bank had the foresight to do this why didn’t politicians in high-income countries respond in a similar fashion? There will be many questions to answer when the dust settles post-COVID-19. I sincerely hope a few political heads roll. We need to take a hard look at whether or not market solutions are really the answer to dealing with existential threats and we need to stop bashing scientists and academics? If we as a society spend billions on academic/intellectual infrastructure we need to maximise its use.

Seow et al. Longitudinal evaluation and decline of antibody responses in SARS-CoV-2 infection. MedRxIV doi: https://doi.org/10.1101/2020.07.09.20148429

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population, it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post-onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow-up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow-up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds. This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

CoI: nil in relation to this post

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

Black Swan?

Is this the black swan I have been looking for?

We need to be able to explain smouldering MS and why pwMS get worse despite having no evident disease activity (NEDA) on DMTs. One of the hypotheses is that something is occurring within the brains and spinal cords of pwMS. I have referred to this in the past as the field hypothesis and have suggested that it could be due to an active virus within the brains of pwMS. I have always made the point that the two viruses with most of the evidence behind them are EBV and HERVs, particularly HERV-W.

This study below strongly suggests that the HERV-W envelope protein may be driving smouldering MS. It would be interesting if the ENV protein is found in SELs (slowly expanding lesions). This study supports our Charcot Project and the urgent need to formally test HAART (highly active antiretroviral therapies) in MS. Our INSPIRE trial, which was negative, was not HAART as it only tested one anti-retroviral and integrase inhibitor.

Do you have the appetite for another push at getting funding for an add-on HAART trial in MS? The case for doing it is compelling both from an epidemiological and basic science perspective.

LET’S DO IT!

Kremer et al. pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis. Proc Natl Acad Sci U S A. 2019 Jun 18

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.