Closing in on the Cause of MS by Dissecting the Immunology of MS Disease-Modifying Therapies
The billion-dollar question is whether or not multiple sclerosis is an autoimmune disease or is it due to a virus?
The billion-dollar question is whether or not multiple sclerosis is an autoimmune disease. I don’t think it is, but I don’t know. I have made a case for EBV being both the trigger and driver of MS disease activity, which is why we need to test EBV antivirals and EBV-directed immunotherapies in MS.
I am giving a keynote presentation, the Whitaker Lecture, at the CMSC-2023 meeting in Denver next week. I was asked to talk on brain health and my marginal gains philosophy of MS but was asked to change my talk a few weeks ago. My talk will now be entitled “Closing in on the Cause of MS by Dissecting the Immunology of MS Disease-Modifying Therapies”. I will be talking about what MS DMTs have taught us about MS and the cause of MS. Some of my talk will cover EBV and what we have planned in the future to explore the EBV hypothesis further.
Although I have been thinking about the issues, the title of this lecture raises for nearly 30 years, putting my ideas into a PowerPoint presentation has been much more challenging than I anticipated. Creating a narrative is very difficult, and building a bridge between the immunology of MS and the MS DMTs to EBV is much more complicated than I realised. My talk is finally taking shape and will include new data, which is exciting.
Yesterday, in an interview, I was asked what it would take to get the broader MS community to adopt EBV as the cause of MS and that EBV latent-lytic infection cycling is driving MS disease activity. I responded that I thought data would change people's minds. A postive clinical trial that an anti-EBV agent in MS is needed. This is why the Atara Bio trial of EBV-targeted cytotoxic T-lymphocytes (CTLs) is so important, with the results due later this year. I have asked myself if this trial is negative would it change things? It will lower the mood in the EBV camp, but I still have concerns about whether or not the strategy of giving CTLs has been optimised.
The problem with using EBV-specific CTLs is that, at present, it is hard to track their survival and half-life once infused. In addition, we don’t have suitable EBV biomarkers to be confident that the CTLs are working in MS and the compartment we need them to target. We need to know if they enter the CNS or, at a minimum, the deep cervical lymph nodes in the neck. Another issue is having enough space in the lymphocyte compartment for donor CTLs. When using CAR T-cells, you must first create space with a depletion protocol, typically cyclophosphamide and fludarabine, before giving the therapy. By creating space in the lymphocyte compartment, engineered autologous cells can engraft, proliferate, find their target, and kill it.
If the Atara Bio EBV-targeted CTL study is negative, is this because the cells didn’t engraft and survive or because they didn’t work (EBV biomarkers unaffected despite engrafted and surviving CTLs) or they worked against EBV but had no impact on MS outcomes (EBV biomarkers affected, but no clinical response)? On the other hand, if the Atara Bio study is positive, this will be the paradigm shift we need, and there will then be a rush to show other therapies are working against EBV. The latter is an argument we have been making for some time, but the message seems to fall on deaf ears.
Another bit of data that would support the EBV-driver hypothesis is to show the autoimmune hypothesis is incorrect. This won’t exclude EBV as the cause of MS because it could still trigger the development of MS in the past (hit-and-run hypothesis) and not be playing an active role in driving the disease.
The argument about whether or not MS is primarily a T-cell or B-cell disease is academic. Almost all the data suggests that both cell types are involved. Clinical trial data indicate that MS outcomes regarding end-organ damage (brain volume loss) and sustained disability improvement that highly-effective therapies targeting T and B cells, i.e. alemtuzumab and AHSCT, are superior.
Another clue is worsening MS and new-onset MS after cancer treatment with the relatively new class of immune checkpoint inhibitors (ICI) treatments. These drugs target cell surface receptors that inhibit T-cell activation. Remove the inhibition, and the threshold for T-cell activation is lowered. About 50% of patients treated with ICI develop immune-mediated complications, including new-onset MS.
The study below identifies 14 cases of MS after ICI, which I suspect is just the tip of the iceberg. The MS induced by ICI appears more aggressive in onset and disease course. Some argue that these cases don’t represent MS but a different disease. I don’t necessarily agree, as an increasing number of people with established MS who develop malignancies requiring treatment with ICI have relapses and rebound disease activity. The sceptics can’t argue that these patients don’t have MS.
The use of ICI in patients with established MS creates a treatment dilemma. They need the ICI to treat their cancer, but how do you manage their MS during the high-risk period when they are on an ICI?
I have in the past recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The potential downside of this strategy is that if she had occult secondaries in her CNS and gut, areas of the body where natalizumab reduced lymphocyte trafficking, natalizumab would prevent her activated T-cells from finding and clearing cancer cells in these organs. However, as bowel cancer rarely metastasizes to the CNS, we thought this was a risk worth taking.
What about the corollary? Instead of ICI, could we stimulate the checkpoint pathways and inhibit MS disease activity? A recent trial of a new monoclonal antibody Peresolimab which stimulates the PD1 pathway and thereby inhibits T-cells from being activated was shown to be positive in rheumatoid arthritis. I would be very interested in seeing if Peresolimab would work in MS. I am sure the antibody developers have MS on their list of potential diseases to try the drug in. If Peresolimab worked in MS, it would prove that MS is likely an autoimmune disease and that T-cells play a role. I don’t need to be convinced about the latter; I think the current evidence is overwhelming.
What about blocking costimulatory pathways, which we know are essential in activating T-cells? In addition to an antigen-specific signal, T-cells need a second activating signal via co-stimulatory molecules to become activated. These costimulatory signals come via antigen-presenting cells, which include B-cells, macrophages and dendritic cells. A trial of Abatacept, a soluble CTLA4-Ig fusion protein that binds to CD80 and CD86 on antigen-presenting cells and thereby blocks the stimulation of the CD28 molecule on T-cells, didn’t work in MS. This is despite it working in rheumatoid arthritis, psoriatic arthritis and polyarticular juvenile idiopathic arthritis. This is another reminder that what works in peripheral arthritides doesn’t necessarily work in MS.
A significant pathway highlighted by our group and others involve CD40 and its binding partnering, the CD40 ligand (CD40L). CD40 is another important costimulatory signal critical in driving T cell activation. Ongoing trials are testing an anti-CD40L monoclonal antibody in MS. I will present the phase 2 results at the CMSC next week and will update you as soon as the results are available. If the results are negative, what will this say about the pathogenesis of MS? Or, on the other hand, if these results are positive will it prove MS is an autoimmune disease unrelated to ongoing EBV infection?
Paper 1
Introduction: Neurological immune-related adverse events are a rare but potentially deadly complication after immune checkpoint inhibitor (ICI) treatment. As multiple sclerosis (MS) is an immune-mediated disease, it is unknown how ICI treatment may affect outcomes.
Methods: We analyzed the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for pembrolizumab, atezolizumab, nivolumab, ipilimumab, avelumab, and durvalumab 2 years prior their FDA approval until December 31, 2017, to include all cases with confirmed diagnosis/relapse of MS. We also included cases reported in the literature and a patient from our institution.
Results: We identified 14 cases of MS with median age of presentation of 52 years. Indications for ICI included melanoma in 7 (36.36%) cases, non-small cell lung carcinoma in 2 (18.18%) cases, 1 case (9.09%) each of pleural mesothelioma, renal cell carcinoma, and colorectal cancer, and unreported in 2 (18.18%) cases. History of MS was confirmed in 8 (57.1%) cases. Median time to beginning of symptoms was 29 days with rapid disease progression; two patients died due to their relapse. Median time for symptom resolution was 8 weeks. Outcomes did not vary by comparing CTLA-4 and PD-1/PD-L1 inhibitors.
Conclusions: Reported MS relapses after ICI are rare, but the adverse events described include rapid neurologic progression and death. Larger and prospective studies are warranted to assess disability and long-term outcomes and outweigh the risks of starting immunotherapy in patients with MS.
Paper 2
Background: Peresolimab is a humanized IgG1 monoclonal antibody designed to stimulate the endogenous programmed cell death protein 1 (PD-1) inhibitory pathway. Stimulation of this pathway would be a novel approach to the treatment of patients with autoimmune or autoinflammatory diseases.
Methods: In this phase 2a, double-blind, randomized, placebo-controlled trial, we assigned, in a 2:1:1 ratio, adult patients with moderate-to-severe rheumatoid arthritis who had had an inadequate response to, a loss of response to, or unacceptable side effects with conventional synthetic disease-modifying antirheumatic drugs (DMARDs) or to biologic or targeted synthetic DMARDs to receive 700 mg of peresolimab, 300 mg of peresolimab, or placebo intravenously once every 4 weeks. The primary outcome was the change from baseline to week 12 in the Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP). The DAS28-CRP ranges from 0 to 9.4, with higher scores indicating more severe disease. The primary comparison was between the 700-mg group and the placebo group. Secondary outcomes included the percentages of patients with American College of Rheumatology 20 (ACR20), ACR50, and ACR70 responses - defined as improvements from baseline of 20%, 50%, and 70% or more, respectively, in the numbers of tender and swollen joints and in at least three of five important domains - at week 12.
Results: At week 12, the change from baseline in the DAS28-CRP was significantly greater in the 700-mg peresolimab group than in the placebo group (least-squares mean change [±SE], -2.09±0.18 vs. -0.99±0.26; difference in change, -1.09 [95% confidence interval, -1.73 to -0.46]; P<0.001). The results of the analyses of secondary outcomes favored the 700-mg dose over placebo with respect to the ACR20 response but not with respect to the ACR50 and ACR70 responses. Adverse events were similar in the peresolimab and placebo groups.
Conclusions: Peresolimab showed efficacy in a phase 2a trial in patients with rheumatoid arthritis. These results provide evidence that stimulation of the PD-1 receptor has potential efficacy in the treatment of rheumatoid arthritis. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04634253.).
Paper 3
Background: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS).
Objective: To evaluate efficacy and safety of abatacept in RRMS.
Methods: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks.
Results: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated.
Conclusion: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.
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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 Barts and The London School of Medicine and Dentistry nor 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 own healthcare professional, who will be able to help you.
Good luck with the presentation, Prof G! Honestly, as someone with MS who is just fighting to survive each day, I don't think this stuff effects me personally. It would have to lead to a treatment that undoes the damage already done to me by MS and the NHS. And be available in my lifetime. And to someone in my socioeconomic position. I'm not optimistic 🤕
Is there any possibility of doing radiolabled acyclovir imaging (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125728/) to see if EBV lytic activity corresponds to MS lesion location or disease activity?