T Cell Vaccination Benefits Relapsing Progressive Multiple Sclerosis Patients: A Randomized, Double-Blind Clinical Trial

<div><h3>Background</h3><p>T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled.</p> <h3>Aim</h3><p>To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial.</p> <h3>Methodology</h3><p>Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10–30×10⁶ T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis.</p> <h3>Results</h3><p>At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (−0.44; p<0.01) and in the 10-meter walking time (0.84 sec; p<0.005). Sixteen of the 17 patients (94.1%) in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment). The proportion of patients with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly.</p> <h3>Conclusions</h3><p>This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/NCT01448252">NCT01448252</a></p> </div

Responsiveness to the Myelin Proteins of enrolled patients.

<p>nd = not done.</p

Demographic data of the patients at inclusion to the study (N = 24).

<p>Demographic data of the patients at inclusion to the study (N = 24).</p

Amelioration of the progression of MS disability, induced by TCV.

<p>The mean EDSS scores of the MS patients at baseline (day of inclusion) and at one year after the first vaccination, in the TCV and the sham/placebo group and the change in the EDSS at one year compared to baseline, are shown. Dark barks indicate the vaccinated patients and the blank bars the placebo group.</p

Beneficial effect of TCV on the proportions of patients with relapses.

<p>The top figure shows the percentages of patients with 0, 1 or 2 relapses in the TCV group and the bottom figure, the percentages in the placebo group. Gray bars represent the relapses during the year preceding the inclusion and the black bars represent the relapses during the one year following treatment.</p

Clinical effects of TCV: Effects on disability and relapse parameters during the one-year follow up.

*<p>All statistical comparisons are between the TCV and placebo groups during the year of the trial.</p

Description of the myelin peptides used for the preparation of TCV.

<p>Description of the myelin peptides used for the preparation of TCV.</p

Consort flow chart.

<p>Consort flow chart.</p

Effects of TCV on the MRI parameters.

*<p>Comparison between the TCV and the placebo group, in terms of change from baseline, using Wilcoxon Signed Ranks test.</p

Downregulation of the anti-myelin T-cell responsiveness to MBP, MOG and PLP, following TCV.

<p>The peripheral blood lymphocytes' responses to the specific myelin proteins that were used for the preparation of TCV were tested using a proliferation assay (as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050478#s2" target="_blank">Methods</a>), at 1 year after the treatment (month 12, black bars) and were compared to the baseline (gray bars) values (before TCV). The responses in 3 representative patients from the TCV and the placebo groups are shown.</p