Abstract
BACKGROUND: Progression independent of relapses (PIRA) is a major therapeutic challenge in multiple sclerosis (MS). Nasal anti-CD3 treats animal models of progressive MS by inducing regulatory T cells (Tregs) that suppress central nervous system (CNS) inflammation and lessen clinical disease. METHODS: Ten patients with non-active secondary progressive MS (naSPMS) that continued to progress on B cell therapy were treated with nasal anti-CD3 (foralumab) for a minimum of six months in an open label study. Safety monitoring included otolaryngology evaluation and neurologic assessments including Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC-4), Modified Fatigue Impact Scale (MFIS), California Verbal Learning Test (CVLT-II) and Low Contract Visual Acuity (LCVA). MRI and microglial translocator protein (TSPO)-PET imaging with [F-18]PBR06 were conducted. Serum and cerebrospinal fluid (CSF) proteomic biomarkers and single cell RNA sequencing of blood was performed to evaluate foralumab-induced immunomodulation. The endpoints of our study were safety, clinical effects, microglial signal and immune measures. RESULTS: All patients stabilized on EDSS scores and three of four patients treated continuously for 12 months had improvement on EDSS. Six of 10 patients had improvement in fatigue on the MFIS scale. There were no treatment-related serious adverse events (SAEs) or severe AEs and no new T2 lesions were observed on MRI. There was a reduction in TSPO-PET signal over six months (p<0.05). Changes in peripheral blood gene expression occurred as early as three months and affected antigen presentation, interferon responses and regulatory pathways in multiple cell types including FoxP3+ Tregs, CD4+ Tcm cells, CD8+ Tem cells, CD14+ and CD16+ monocytes and B cells. TGFβ expression was increased across cell multiple subsets. INTERPRETATION: These findings identify a novel, non-toxic immune based therapy for the treatment for PIRA that acts by the induction of a regulatory immune responses and dampens microglial inflammation. Double blind placebo-controlled trials are warranted to explore nasal foralumab for the treatment of naSPMS.