Antigen-Specific Tolerance by Autologous Myelin Peptide–Coupled Cells: A Phase 1 Trial in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1–20, MOG35–55, MBP13–32, MBP83–99, MBP111–129, MBP146–170, and PLP139–154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 109) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.

Harnessing Nanoparticles for Immune Modulation

“…The 'Holy Grail' of autoimmune therapy is the restoration or induction of robust peripheral immune tolerance in only those cells causing disease. The use of apoptotic cells to induce tolerance was uncovered originally in 1979 [79] and has shown promise in an early clinical study [80], However, the use of cells has numerous manufacturing, cost, and patient accessibility issues. The serendipitous discovery that negatively charged NPs target specific scavenger receptors and localize to the same regions of the spleen, similar to apoptotic cells, catalyzed the development of a synthetic cell replacement that could carry antigen for immune tolerance induction [6,8,81].…”

“…Identification is further complicated in multiple sclerosis (MS), for example, by the fact that the appropriate target antigen may change over time due to epitope spreading. Nevertheless, in some disorders, including celiac disease, MS, and type 1 diabetes, numerous antigens have been identified [80,[82][83][84]. Another potential strategy, which both harnesses the natural mechanisms that may have initiated autoimmunity and obviates the need for knowing the precise epitopes, may be the use of full-length proteins.…”

Biodegradable antigen-associated PLG nanoparticles tolerize Th2-mediated allergic airway inflammation pre- and postsensitization

“…Ag-SPs induce tolerance in a variety of immune disorders, and Ag-conjugated autologous leukocytes have shown initial promise in clinical trials of patients with multiple sclerosis (MS) (5). However, the need for autologous cells to be isolated and manipulated before each treatment limits the broad clinical application of such a treatment.…”

Immunology: A tolerant approach

“…Martin's clinical team gave nine patients a single injection of the manipulated immune cells, in escalating doses. The treatment seems to be safe, and the four patients receiving the highest doses showed a reduction in the number of T cells targeting self-antigens 9 . "That was a very positive proof-ofconcept study, " says Nepom, who was not involved in any of the trials.…”