Administration of CD4⁺CD25^highCD127^-FoxP3⁺ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1...

Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (T_conv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4⁺CD25^highCD127^-FoxP3⁺ T regulatory (T_reg) cells may inhibit this destruction through suppressive activity exerted on T_conv cells.

We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous T_reg cells for relapsing-remitting MS. The patients received either expanded ex vivo T_reg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 10⁶ T_reg cells/kg of body weight) or freshly isolated T_reg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 10⁶ T_reg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up.

No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of T_reg cells or T_conv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, T_reg cells in all patients consisted of two different phenotypes: peripheral T_reg cells Helios(-) (≈ 20%) and thymic T_reg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.

No serious adverse events were reported in the 14 patients with MS treated with T_reg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety.

EudraCT: 2014-004320-22; registered 18 November 2014.