Sustained freedom from disease activity in secondary progressive multiple sclerosis by targeting invariant NKT cells: a phase 2 trial of OCH
Preprint
Abstract
Multiple sclerosis (MS) therapies primarily rely on lymphocyte depletion or trafficking blockade, carrying risks of systemic immunosuppression; however, such treatments have limited efficacy in secondary progressive multiple sclerosis (SPMS). Thus, drugs that target stage-specific inflammation without broad immunosuppression are an unmet clinical need. In this double-blind, placebo-controlled phase II trial, 30 patients with relapsing MS received weekly oral OCH or placebo for 24 weeks. In the pre-specified SPMS subgroup (n=12), OCH achieved complete relapse prevention (p=0.0003), prolonged relapse-free survival (p=0.0079), no new lesions (0/6), with no evidence of disease activity (NEDA-3) in 5/6 patients. In comparison, for the placebo-treated group, 5/6 patients suffered relapses, 2/6 patients developed new lesions, and no placebo-treated SPMS achieved NEDA-3. Invariant natural killer T (iNKT) cells, a regulatory lymphocyte population that is numerically and functionally impaired in MS, are a potential target for MS therapy. Glycolipid OCH is a selective iNKT cell stimulator, skewing the cytokine environment towards Th2. OCH treatment resulted in increased IL-4-producing Th cells in patient peripheral blood while decreasing pathogenic GM-CSF-producing Th cells. Parallel studies in mouse models of MS (EAE) corroborated this mechanism and further revealed that OCH activated gut iNKT cells. Disease amelioration by OCH depended on IL-4 and its efficacy was further enhanced by depletion of B cells. These data revealed the gut-brain axis mediation of progressive-stage pathology distinct from relapsing-remitting MS. Findings from this bidirectional translational study uncover mechanistic differences between SPMS and other types of MS and highlight divergent roles for B cells and Th cells. Furthermore, OCH exerts its therapeutic benefit via targeting mechanisms that are distinct from currently available drugs; exploiting iNKT cell regulatory potential to reprogram pathogenic T helper responses without lymphocyte depletion. The unique yet effective nature of OCH treatment positions it as an attractive future oral therapy for SPMS. One Sentence Summary: The iNKT cell activating ligand OCH suppresses disease activity selectively in secondary progressive MS in a phase II clinical trial, revealing stage-specific IL-4-mediated immune cell interactions in MS pathology.Keywords
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