Samia Khoury | Harvard University | Boston, MA

Brigham and Women's Hospital | Boston, MA

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) initiated by autoreactive CD4+ T cell recognizing and responding to myelin antigens. Our understanding of the immunopathogenesis of MS implicates T cell activation as an important step in the pathogenesis of this autoimmune disease. In experimental autoimmune encephalomyelitis (EAE), the animal model of MS, treatment of animals with CTLA4Ig, a fusion protein that binds and blocks B7 interaction with CD28, suppresses EAE.

We also found that expression of CD28 in the CNS of mice undergoing EAE correlated with disease activity. More importantly, B7 molecules are expressed in plaques from MS brain. Initial studies in humans with CTLA4Ig for the treatment of psoriasis showed that this treatment could safely be administered to patients and appeared to be efficacious.

Our hypothesis is that treatment with CTLA4Ig will arrest the disease if administered early in the course of MS and provides a novel conceptual approach to treat MS with the intent to abort the disease. Our primary objective in this study is to evaluate the safety and immunologic effects of CTLA4Ig therapy in MS. The study will include 3 dose groups (4 patients each) starting with an induction therapy of 3 daily doses followed by 2 monthly treatments of CTLA4Ig with a total duration of study of 4 months. This phase 1 study is not designed to test efficacy but only safety and immunologic responses in treated patients. MRI measures of disease activity (T2 lesion volume, number of gadolinium (GD) enhancing lesions and progression of atrophy) will also serve as safety measures and may provide hints for efficacy information to help design Phase II studies. This clinical study will be accompanied by extensive immunologic studies in order to understand the immunomodulatory functions of CTLA4Ig in MS patients. The immunologic studies will focus on 4 areas of investigation: 1) to look for change in activation state of I cells before and after treatment, 2) to investigate the effect of treatment on markers of inflammation that have been associated with disease activity in MS, 3) to investigate the effect of treatment on the precursor frequency of myelin reactive cells and 4) to investigate the effect of treatment on immune function in vivo.