Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Nash, Richard A.; Hutton, George J.; Racke, Michael; Popat, Uday; Devine, Steven M.; Georges, George E.; Griffith, Linda M.; Muraro, Paolo A.; Openshaw, Harry; Sayre, Peter H.; Stüve, Olaf; Arnold, Donald M.; Spychala, Meagan; Lim, Noha; Malhotra, Sachin; Phippard, Deborah; Wundes, Annette; Kraft, George H.; Bowen, James D.

doi:10.1016/j.bbmt.2012.11.062

Cited by 4 publications

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“…12 The US HALT-MS trial preliminary results in 25 patients with highly active, treatment-refractory RRMS have reported a 77% event-free survival at 2 years post-HSCT utilizing a stringent composite endpoint that included relapses, new MRI lesions and progression of neurological disability. 23 …”

Section: Introductionmentioning

confidence: 99%

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper

et al. 2012

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Background:Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1–2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing–remitting phase than in those in the secondary progressive stage.Objectives:An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments.Conclusions:Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

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Section: Introductionmentioning

confidence: 99%

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper

et al. 2012

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Haematopoietic Stem Cells for the Treatment of MS

Abrahamsson

Mattoscio

Muraro

2013

Multiple Sclerosis Immunology

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T cell repertoire following autologous stem cell transplantation for multiple sclerosis

Muraro¹,

Robins²,

Malhotra³

et al. 2014

J. Clin. Invest.

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Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCRβ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4 + and CD8 + T cell repertoires. In CD4 + T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8 + clones were not effectively removed, and the reconstituted CD8 + T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies. IntroductionWhen employed for immunomodulation, the goal of autologous hematopoietic stem cell transplantation (HSCT) is to create a non-autoreactive immune compartment by altering the immune repertoire and/or function of autoreactive cells (1-3). Using T cell receptor excision circle analysis in HSCT-treated MS patients, we showed previously that even in adults, thymic output contributed to the post-treatment TCR repertoire (2, 4) and that this, plus expansion of residual cells not eliminated during conditioning, regenerated the T cell compartment (5).However, the clonal specificities of a regenerated repertoire following high-dose immunosuppressive therapy (HDIT) and autologous HSCT have not been well explored, as previous studies used CDR3 spectratyping for TCR clonal analysis, which made it impractical to sequence more than several dozen TCRs. Only a single patient receiving HSCT for autoimmune disease (ankylosing spondylitis) has had a fuller analysis of their TCR repertoire reported (6). Here, as part of a new phase II trial for poor-prognosis MS (see Methods), we have taken advantage of high-throughput deep TCRβ chain sequencing (7) to directly assess millions of TCRs per individual before and at two time points after autologous HSCT in a cohort of 24 patients.

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Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: 2-Year Follow-up Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Cited by 4 publications

References 0 publications

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper

Haematopoietic Stem Cells for the Treatment of MS

T cell repertoire following autologous stem cell transplantation for multiple sclerosis

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