Preliminary Trial of T-cell Receptor Vaccination in MS: Is Relief a Shot Away?
ABSTRACT & COMMENTARY
Source: Vandenbark AA, et al. Treatment of multiple sclerosis with T-cell receptor peptides: Results of a double-blind pilot trial. Nature Med 1996;2:1109-1115.
For many years now, investigators have been able to alter the course of the animal model of multiple sclerosis (MS), experimental autoimmune encephalo-myelitis (EAE), by targeting the T-cells specific for myelin basic protein (MBP), the oligodendroglial protein used to induce the disease. The encephalitogenic T-cells in EAE were found to have a highly restricted pattern of T-cell receptor (TCR) usage, Va2 and Vb8.2, which when eliminated by specific monoclonal antibodies could arrest or prevent EAE. Another later approach was to "vaccinate" the animal with attenuated Va2/Vb8.2 T-cells, or even synthetic peptides corresponding to the Vb8.2 TCR, generating an immune response in the animal toward its own T-cells which protected against the development of EAE.
This strategy was applied in a small, double-blinded study in 23 HLA-DR2+ MS patients with chronic progressive disease (EDSS 3.5-6.5), by monthly vaccinations of a 20 amino acid peptide corresponding to TCR Vb5.2. The TCR Vb5.2 was selected because some researchers had previously suggested that there was overexpression of Vb5.2 "MBP-specific" T-cells in the blood and brain plaques of MS patients (PNAS 1991;88:9161-9165). Over a one-year period, of the 17 patients receiving the peptide vaccine, eight were stable, eight were worse, and one improved. Of the six patients receiving an inert placebo vaccine, three were stable, two were worse, and one improved. However, when the investigators broke down the treated group of 17 patients into TCR peptide vaccine "responders" (i.e., a smaller subset of only 6 patients that successfully developed an immune response against the Vb5.2 peptide), five were stable and one improved. Possibly owing to the small sample size, there was no statistically significant difference between the TCR peptide vaccine responders and the placebo group. Of the "nonresponders" and placebo patients that worsened clinically, there appeared to be a correlation with increasing frequencies of MBP-specific T-cells (P = 0.024) over a 12-month period.
Many different therapeutic approaches have recently been explored in treating MS, including the cytotoxic immunosuppressants methotrexate and cladribine (Neuro Alert 1995;13:57-58), and the novel immunomodulatory therapies interferon-beta and copolymer (Neuro Alert 1996;14:74-75), linomide (Neuro Alert 1996;15:21-22), and oral myelin immune-tolerization (Neuro Alert 1993;11:67). This pilot study by Vandenbark and colleagues is a logical extension into human MS subjects of TCR vaccination experiments effectively applied in EAE rodent models of disease, although many scientists question the relevance of EAE to MS and the importance of MBP-reactive T-cells to brain pathology in MS. Also controversial is whether there is any definable restriction or expansion of the immune response in MS to a limited T-cell repertoire that would be amenable to this targeted TCR peptide vaccine approach.
Putting these important criticisms aside, this study does establish the feasibility of safely inducing an immune regulatory response against a TCR peptide, although demonstrating a clinical benefit for MS may require a more effective TCR vaccine and a larger series of patients with longer follow-up. There are considerable difficulties of documenting clinical outcomes in MS treatment trials, depending on the primary and secondary end points selected and the composite scales of disability measurement used. The absence of independent, objective markers of disease activity such as serial brain MRI scans also limits the conclusions of this study. Nonetheless, the results of this early report are encouraging and indicate the increasing role such immunomodulatory therapy will play in clinical practice in years to come. We eagerly await the results of an expanded phase 2 clinical trial now in progress.