To T or not to T (2)

T

Prof G what happens to MS disease activity if you stimulate T-cells?

About 2 years ago I attended a grand round during which a patient with a history of RRMS had had a catastrophic relapse after receiving ipilimumab for metastatic melanoma. The patient has a massive brain stem relapse and her MRI showed multiple Gd-enhancing lesions with several pseudotumoral lesions. She was in a bad way. Interestingly, this case was not unique as a very similar case had been published. In addition, there are series of other examples of ipilimumab and other immune checkpoint inhibitors exacerbating and/or triggering autoimmune diseases including an MS-like disease. I say MS-like because we don’t know for sure if these cases will turn out to have classic MS on biopsy, or at post-mortem, to prove they have definite MS according to a conventional definition of the disease.

Ipilimumab belongs to the class of drugs called ‘checkpoint inhibitors’ that are designed to remove one of the immunological brakes that control T-cell activation. Ipilimumab is one of many T-cell stimulants that have revolutionised the care of patients with various different cancers. Ipilimumab is a very smart drug it blocks CTLA-4, a cell surface molecule on T cells, which normally blocks or downregulates T cell activation when it binds to CD80 and CD86 on antigen-presenting cells. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity.

So what has this really got to do with MS? Well, these cases are telling us in a not so subtle way that by stimulating T-cells we can exacerbate MS. In other words, T-cells are probably still active in established MS. What this experiment is not telling us is which population of T-cells is the culprit as CD4+, CD8+ and T-regulatory cells express CTLA-4 and are hence affected by Ipilimumab. Nor is it telling us about the APC side, which APC is stimulating the T-cells. Is it the B-cell, the macrophage/microglia or another APC?

The moral of this story is that it takes two to tango; the T-cell and its APC. The question is which APC is the preferred partner for the T-cell in MS. Based on the evidence the B-cell seems to be the dominant partner, but who knows in the presence of peripheral B-cell depletion other less dominant partners may take to the floor.

Gettings et al. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler. 2015 Apr;21(5):670.

56-year-old male, diagnosed in December 1997 with RRMS. Treated with glatiramer acetate in February 1998. Relatively good response to GA with only sensory relapses. In 2005 methotrexate was added. His MS stabilized and he was free of relapses from 2005 to 2013 with a slight increase in disability from an Expanded Disability Status Scale (EDSS) score of 1 to 1.5. In September 2009 diagnosed with melanoma. He had a recurrence in November 2012 with metastases to soft tissue and lymph nodes. He was started on ipilimumab. Methotrexate and glatiramer acetate were stopped prior to initiating ipilimumab. Within one month, he presented with subacute onset of left lower extremity hemiparesis, gait dysfunction and ataxia. An MRI revealed a new left centrum semiovale enhancing lesion consistent with active demyelination. His symptoms improved with high dose methylprednisolone. Ipilimumab was continued. In May 2013 he was readmitted for transient left-sided weakness and ataxia. MRI revealed an enhancing lesion in the right corona radiata. Follow-up imaging revealed a second enhancing lesion in the right frontal lobe and he was restarted on glatiramer acetate and steroids.

About the author

Gavin

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

17 comments

    • Yes, but the data is contradictory about whether or not EBV within the CNS is driving MS disease activity. It is also very difficult to prove.

      • I gave the Charcot lecture earlier this year at the NIH. In the lecture, I made the point that the epidemiology and biology of MS are coming together around the B-cell and EBV and that it is looking increasingly likely that EBV is the cause of MS.

        Yes, but the data is contradictory about whether or not EBV within the CNS is driving MS disease activity. It is also very difficult to prove.

        A month was past

        Which one i choose?

        obrigado

  • Single dose of anti–CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance
    Virginia A. Pedicord,a Welby Montalvo,a Ingrid M. Leiner,b and James P. Allisona,

    CTLA-4 is a second receptor for the B cell activation antigen B7.
    P S Linsley, W Brady, M Urnes, L S Grosmaire, N K Damle, J A Ledbetter
    DOI: 10.1084/jem.174.3.561 | Published September 1, 199

    Memory B Cells and Response to Abatacept in Rheumatoid Arthritis.
    Gazeau P1,2, Alegria GC1,2, Devauchelle-Pensec V2,3, Jamin C1,3, Lemerle J1, Bendaoud B1,3, Brooks WH4, Saraux A2,3, Cornec D2,3, Renaudineau Y5,6. Clin Rev Allergy Immunol. 2017 Oct;53(2):166-176
    Abstract
    Abatacept is a fusion protein (CTLA4-Ig) and therapeutic molecule labeled for the treatment of rheumatoid arthritis (RA). Abatacept acts both by disrupting the CD28-mediated activation of T cells and by interacting with CD80/CD86 molecules present on antigen presenting cells such as monocytes and memory B cells. Accordingly and to evaluate clinical and biological parameters associated with response to abatacept, a retrospective monocentric study was conducted in 43 patients with RA, and the clinical response was evaluated at 6 months according to EULAR response criteria. Median age of the patients was 59.8 ± 15.1 years including 35 females and 8 males. At baseline, no difference was observed between non-responders (NR, n = 11), moderate responders (MR, n = 21), and good responders (GR, n = 11) to abatacept with regards to demographic, biological, and clinical characteristics of the patients (age, sex, anti-CCP, RF, FcγR3A V158F polymorphism, and C3/C4 complement reduction).

    Moreover, peripheral blood lymphocyte phenotyping was performed by flow cytometry revealing in 30 RA patients compared to controls (n = 45; median age 56.7 ± 13.5 years) that the initial CD19+ B cell count was reduced in NR and MR but not in GR. No differences were observed with regards to total lymphocyte, T cell, and NK cell counts. Next, we further explored the effects of abatacept on B cell subsets (IgD/CD38 in panel 1 and IgD/CD27 in panel 2) and observed that the basal level of CD38+ and/or CD27+ memory B cell count was important for an abatacept response and that a selective effect of abatacept was observed on memory B cells after 6 months. In conclusion, and although these data need to be confirmed in an independent cohort, our data support a role for memory B cells in the mechanism of action of abatacept in RA.

    ACCLAIM: A randomized trial of abatacept (CTLA4-Ig) for relapsing-remitting multiple sclerosis.
    Khoury SJ, Rochon J, Ding L, Byron M, Ryker K, Tosta P, Gao W, Freedman MS, Arnold DL, Sayre PH, Smilek DE; ACCLAIM Study Group. Mult Scler. 2017 Apr;23(5):686-695. 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.

    Does a swallow make a summer?

    • Yep, a swallow makes a summer provided you can prove that it didn’t stay behind and survive the winter.

      These results could be compatible with memory B cells presenting antigen centrally, i.e. the APC-T-cell interaction is within the CNS. This could explain natalizumab rebound and the ability of anti-CD20 to prevent rebound.

      In RA the CNS is not relevant as the APC-T-cell interaction will happen in the periphery.

      I would be interested to know how much Abatacept crosses the blood-brain-barrier; I bet not much therefore APC in the CNS may be unaffected by the treatment. However, the corollary of this is T-cell activation; in MS this can occur in the periphery. However, once T-cells are activated they will cross the BBB and interact with professional APCs within the CNS. Therefore, inhibiting peripheral and not CNS, APC-T-cell interactions does not argue against the T-cell hypothesis, nor the observation that checkpoint inhibitors are able to trigger MS disease activity presumably in the periphery. Presumably, ipilimumab crosses the BBB poorly and is unlikely to have an impact on T-cells within the CNS already.

      It is clear that as our hypotheses are evolving we will need to test them in the lab.

  • Characteristics and treatment of new-onset arthritis after checkpoint inhibitor therapy
    Jan Leipe1, Lisa A Christ1, Andreas P Arnoldi2, Erik Mille3, Frank Berger2, Markus Heppt4, Ilana Goldscheider4, Diego Kauffmann-Guerrero5, Rudolf M Huber5, Claudia Dechant1, Carola Berking4, Hendrik Schulze-Koops1 and Alla Skapenko1.

    It is not only MS after these drugs

  • Cart t cell theraphy is also neurotoxic

    Endothelial Activation and Blood–Brain Barrier
    Disruption in Neurotoxicity after Adoptive
    Immunotherapy with CD19 CAR-T Cells

    Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric
    antigen receptor–modified T (CAR-T) cells can be complicated by neurologic
    adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19
    CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high
    CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated
    with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of
    endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased
    blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from
    high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress
    and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular
    disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation
    were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity

    Cancer Discov;
    7(12); 1–16. ©2017 AACR.

    • CAR-T cells are engineered to be antigen specific. I am not aware of them making MS worse. Neurotoxicity due to CAR-T cells seems to be due to a bystander effect from a cytokine release syndrome.

  • What happens to MS disease activity if you inhibit T-cell activation with ciclosporin or the other anti-organ rejection drugs?

    • Interesting question. Yes, azathioprine, mycophenolate and cyclosporin, less so for tacrolimus, have all be shown to have moderate effects on MS disease activity. But these agents are not T-cell specific so you can’t draw too many conclusions from the data.

      • I gave the Charcot lecture earlier this year at the NIH. In the lecture, I made the point that the epidemiology and biology of MS are coming together around the B-cell and EBV and that it is looking increasingly likely that EBV is the cause of MS.

        Yes, but the data is contradictory about whether or not EBV within the CNS is driving MS disease activity. It is also very difficult to prove.

        A month was past

        Which one i choose?

        obrigado
        Anti-thymocyte globulin

        • Both. EBV may be the trigger and works in a hit and run fashion. We have no idea if EBV continues to drive MS disease activity. Once autoimmunity is established, that is if MS is an autoimmune disease, you need a complex approach to managing the disease.

      • Atg

        The EBMT has developed several trials of autografts in
        patients with autoimmune disorders, including multiple
        sclerosis, Crohn’s disease, systemic sclerosis, and systemic
        lupus erythematosus [256]. These trials are based on the
        hypothesis that high-dose therapy combined with rATG
        can ‘reset’ the immune system and induce long-term
        remission. rATG is typically given at the time autologous
        stem cells are re-infused, in combination with high-dose
        cyclophosphamide (200 mg/kg) or high-dose combination
        chemotherapy (BEAM). This hypothesis has been proven
        in several phase II trials, and very recently in three prospective,
        randomized trials which compared this procedure
        with best available treatment—the ASTIM study in multiple
        sclerosis [257], ASTIC for Crohn’s Disease, and
        ASTIS for systemic sclerosis. The EBMT registry of
        autoimmune disorders now has data on 1,700 patients, and
        the field is moving fast, with increasing numbers of patients
        being treated following the positive results of these randomized
        trials.

        New Directions for Rabbit Antithymocyte Globulin
        (Thymoglobulin) in Solid Organ Transplants, Stem Cell
        Transplants and Autoimmunity

        DOI 10.1007/s40265-014-0277-6

    • Cyclosporin A had a marginal effect and induced some kidney problems, but the problem was that it was trialled in people with SPMS and importantly Cyclosporin is actively pumped out of the brain by at least three different drug pumps

  • Thanks Prof G. If this article is right. Basically all those on b therapies are only delaying their disease progress. I’m not a fan of b therapy but we know this is not the case as shown by Rituximab use in Sweden. Its feels the tango between and T and b is most virulent combination. MD b therapies is your baby. What’s your take?

    • I think you need to interpret everything as being circumstantial at the moment. What we are proposing is a hypothesis, i.e. that T&B cell depletion is more effective than B-cell depletion alone. The T&B cell depleters take out both the afferent and efferent arms of the immune system; the cost of this is severe and potentially life-threatening complications. The B-cell depleters leave the efferent arm (T-cells) and some of the afferent arm (APCs) intact, which does not get completely on top of the inflammation and results in ongoing low-grade smouldering inflammation. It is clear that B-cell depletion is a much safer option. Our claim to back up this hypothesis is based on the end-organ damage or brain volume loss data rather than the NEDA data.

By Gavin

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