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J Crohns Colitis. 2018 Jan 24;12(2):188-196. doi: 10.1093/ecco-jcc/jjx128.

Effect of PF-00547659 on Central Nervous System Immune Surveillance and Circulating β7+ T Cells in Crohn's Disease: Report of the TOSCA Study.

Author information

1
Academic Medical Center, Amsterdam, The Netherlands.
2
Leuven University Hospital, Leuven, Belgium.
3
Medical University of Vienna, Vienna, Austria.
4
Hôpital Saint-Louis, Université Paris Diderot, Paris, France.
5
University of Lille, Lille, France.
6
Erasme Hospital, Free University of Brussels, Brussels, Belgium.
7
University of California San Diego, La Jolla, CA, USA.
8
Charité Medical School, Humboldt-University of Berlin, Berlin, Germany.
9
Mellen Center for MS Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.
10
Kimberton Drug Development Consulting, Phoenixville, PA, USA.
11
Pfizer, Cambridge, MA, USA.
12
McMaster University, Hamilton, ON, Canada.
13
Neurology Section, VA North Texas Health Care System, Dallas, TX, USA.
14
Southwestern Medical Center, University of Texas, Dallas, TX, USA.
15
Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Germany.

Abstract

Background and Aims:

Progressive multifocal leukoencephalopathy [PML], a brain infection associated with anti-integrin drugs that inhibit lymphocyte translocation from bloodstream to tissue, can be fatal. Decreased central nervous system [CNS] immune surveillance leading to this infection has been reported in patients with multiple sclerosis or Crohn's disease treated with anti-integrin antibody natalizumab. PF-00547659 is an investigational human monoclonal antibody for inflammatory bowel disease, targeted against α4β7-mucosal addressin cell-adhesion molecule-1 [the integrin ligand selectively expressed in the gut]. We hypothesised that this selective agent would not affect central nervous system immune surveillance.

Methods:

Cerebrospinal fluid from five healthy volunteers, and from 10 patients with Crohn's disease previously treated with immunosuppressants, was evaluated to assess the feasibility of the study. Subsequently, 39 patients with active Crohn's disease and previous immunosuppression were evaluated over 12 weeks of PF-00547659-induction therapy. We measured total lymphocytes, T cell subsets in cerebrospinal fluid, and circulating β7+ memory cells. Disease activity was assessed using the Harvey-Bradshaw Index.

Results:

Patients treated with PF-00547659 had no reduction of cerebrospinal fluid lymphocytes, T-lymphocyte subsets, or CD4:CD8 ratio, whereas circulating β7+ memory cells increased significantly. A total of 28/35 [80%] patients had a clinical response and 27/34 [79%] had disease remission. Treatment-related adverse events, none serious, were reported in 23/49 [47%] patients.

Conclusions:

In patients with active Crohn's disease, natalizumab therapy increases the risk for PML, and the increased risk is thought to be associated with iatrogenic leukopenia within the CNS. PML under PF-00547659 may be a lesser concern, as this agent did not reduce lymphocytes or T cell subsets in the cerebrospinal fluid.

KEYWORDS:

Crohn’s disease; MAdCAM-1; PF-00547659; immune surveillance; inflammatory bowel disease

PMID:
28961770
PMCID:
PMC5881743
DOI:
10.1093/ecco-jcc/jjx128
[Indexed for MEDLINE]
Free PMC Article

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