Determination of Immune Surveillance in Cerebrospinal Fluid (CSF) in Patients with Crohnʼs Disease: Initial Results of the TOSCA Study

Abstract

Purpose: The risk of progressive multifocal leukoencephalopathy (PML) is increased by natalizumab, a therapeutic antibody used for multiple sclerosis and crohn's disease (CD) that blocks both α4β1 and α4β7 integrins, and thereby inhibits both central nervous system (CNS) and gut trafficking of lymphocytes. Natalizumab therapy is associated with marked reduction in CSF total and CD4+ lymphocytes, and an inverted CD4:CD8 ratio, which indicates deficient CNS immune surveillance, the putative mechanism contributing to PML caused by JC virus infection/reactivation. The investigational drug PF-00547659 (PF) is a fully human anti-MAdCAM monoclonal antibody designed to reduce lymphocyte homing exclusively to the gut, for the treatment of inflammatory bowel disease (IBD). Because of the low incidence of natalizumab associated PML, comparing risk between these drugs in clinical trials is difficult. However, 6 weeks after one injection of natalizumab, a dramatic drop in CSF lymphocytes and CD4 cells occurs. Thus, an additional approach to assess drug-induced PML risk may be to determine the effect of a new agent on CNS T lymphocytes. The purpose of this study is to assess whether PF alters trafficking of the lymphocyte population to the CNS, reflecting immune surveillance in CD patients. Methods: TOSCA is an open-label study of PF designed in two cohorts. Cohort 1 explored baseline CSF values at two different lumbar puncture (LP) visits before administration of PF, whereas cohort 2 is designed to investigate CSF composition before and during treatment with PF. We present here the data from Cohort 1, along with concurrent data from five healthy subjects. CSF from adults with moderately-to-severely active CD, who failed prior treatment with immunosuppressants (IS) and anti-TNF, was analyzed by FACS. Results: Of 10 CD pts, eight were men, age (mean±sd) was 40.8±16.0 years, CD duration was 13.5±6.1 years, and HBI was 8.6±2.8 for seven patients (three had stomas). Data from two patients were discarded because of inaccurate cell counting. Three patients did not have a 2nd LP because of headache. FACS data, in cells/mL, are shown in the table.Table: Table. Geometric mean values (CV%)Conclusion: CSF lymphocyte counts are similar between healthy subjects and patients with moderate-to-severe CD. Repeat testing showed stable CSF lymphocyte populations, indicating lack of inflammatory changes after LP. This approach offers promise in assessing risk of anti-integrin therapy. Disclosure - Fabio Cataldi Employee, of Pfizer inc. Kenneth Gorelick Employee of Pfizer inc Sunday Rivers Employee of Pfizer inc Mina Hassan-Zahraee Employee of Pfizer inc John Cheng Employee of Pfizer inc Bo Jin Employee of Pfizer inc Jenny Yanhua.Zhang Employee of Pfizer inc William Sandborn Consultant Pfizer Walter Reinisch Consultant Pfizer Geert D'Haens Consultant Pfizer Andre Van Gossum None Richard Ransohoff None Olaf Stuve None. This research was supported by an industry grant from Pfizer Inc.