CTLA4Ig treatment in patients with multiple sclerosis

Viglietta, Vissia; Bourcier, Kévin; Buckle, Guy J.; Healy, Brian C.; Weiner, Howard L.; Hafler, David A.; Egorova, Svetlana; Guttmann, Charles R.G.; Rusche, James R.; Khoury, Samia J.

doi:10.1212/01.wnl.0000325915.00112.61

Cited by 91 publications

(70 citation statements)

References 34 publications

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“…In a phase 1 therapeutic trial, the CTLA4 pathway was targeted with soluble CTLA4‐Ig, a CTLA4 agonist 26. No adverse safety signals were observed in the pilot trial 26.…”

Section: Discussionmentioning

confidence: 99%

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CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Gerdes¹,

Held²,

Beltrán³

et al. 2016

Annals of Neurology

101

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We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4‐blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T‐cell type MS. Quantitative next generation sequencing of T‐cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T‐cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294–300

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“…In a phase 1 therapeutic trial, the CTLA4 pathway was targeted with soluble CTLA4‐Ig, a CTLA4 agonist 26. No adverse safety signals were observed in the pilot trial 26.…”

Section: Discussionmentioning

confidence: 99%

“…In a phase 1 therapeutic trial, the CTLA4 pathway was targeted with soluble CTLA4‐Ig, a CTLA4 agonist 26. No adverse safety signals were observed in the pilot trial 26. An NIH‐sponsored follow‐up phase 2 trial of CTLA4‐Ig is currently underway (https://clinicaltrials.gov/ct2/show/NCT01116427?term=CTLA-4+Ig+multiple+sclerosis&rank=1).…”

Section: Discussionmentioning

confidence: 99%

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Gerdes¹,

Held²,

Beltrán³

et al. 2016

Annals of Neurology

101

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“…On one hand, T-cell activation facilitated by B7 costimulation has become widely exploited with B7-neutralizing therapies in a variety of human autoimmune disorders (2)(3)(4)(5)(6). On the other hand, B7 costimulation also maintains Tregs at expanded levels that averts multiorgan systemic autoimmunity (9,10).…”

Section: Discussionmentioning

confidence: 99%

“…Reciprocally, soluble recombinant formulations of the natural high-affinity B7 ligandcytotoxic T-lymphocyte antigen 4 fused with human Ig (CTLA4-Ig), which blocks B7 costimulation-are efficacious in neutralizing aberrant T-cell activation in autoimmune disorders such as rheumatoid arthritis and juvenile idiopathic arthritis (2). Ongoing studies suggest that these therapeutic benefits also extend to many other types of autoimmunity including psoriasis, systemic lupus erthematosus, multiple sclerosis, and type 1 diabetes (3)(4)(5)(6). Interestingly, however, the protective benefits of B7 blockade are not universal as CTLA4-Ig is distinctively nonefficacious for inflammatory bowel disease (7) and can induce intestinal inflammation among individuals with unrelated autoimmune disorders (8).…”

mentioning

confidence: 99%

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Luo¹,

Jiang²,

Chaturvedi³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The costimulatory B7-1 (CD80)/B7-2 (CD86) molecules, along with T-cell receptor stimulation, together facilitate T-cell activation. This explains why in vivo B7 costimulation neutralization efficiently silences a variety of human autoimmune disorders. Paradoxically, however, B7 blockade also potently moderates accumulation of immune-suppressive regulatory T cells (Tregs) essential for protection against multiorgan systemic autoimmunity. Here we show that B7 deprivation in mice overrides the necessity for Tregs in averting systemic autoimmunity and inflammation in extraintestinal tissues, whereas peripherally induced Tregs retained in the absence of B7 selectively mitigate intestinal inflammation caused by Th17 effector CD4 + T cells. The need for additional immune suppression in the intestine reflects commensal microbe-driven T-cell activation through the accessory costimulation molecules ICOSL and OX40L. Eradication of commensal enteric bacteria mitigates intestinal inflammation and IL-17 production triggered by Treg depletion in B7-deficient mice, whereas re-establishing intestinal colonization with Candida albicans primes expansion of Th17 cells with commensal specificity. Thus, neutralizing B7 costimulation uncovers an essential role for Tregs in selectively averting intestinal inflammation by Th17 CD4 + T cells with commensal microbe specificity.

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“…Anti-CTLA-4 treatment increased clinical signs of EAE in animal models [145,146]. Abatacept has showed safety and favorable immunological effects in a phase I clinical trial in patients with RRMS [147], while an initial placebo-controlled phase II trial in 219 patients was halted prematurely because of an increased relapse rate and MRI activity in an abatacepttreated group [148]. However, a post-hoc analysis revealed that patients in this treatment arm had a higher baseline activity at the time of study inclusion, providing the rationale for another attempt a few years later.…”

Section: Anti-ctla-4-directed Therapy (Abatacept)mentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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CTLA4Ig treatment in patients with multiple sclerosis

Abstract: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

Cited by 91 publications

References 34 publications

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

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CTLA4Ig treatment in patients with multiple sclerosis

Abstract: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

Cited by 91 publications

References 34 publications

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 + T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Contact Info

Product

Resources

About

Commensal microbes drive intestinal inflammation by IL-17–producing CD4 ⁺ T cells through ICOSL and OX40L costimulation in the absence of B7-1 and B7-2