Establish Tolerance in MS with myelin-peptide coupled red blood cells - the Phase Ib ETIMSredtrial
ECTRIMS Online Library. Lutterotti A. 09/13/19; 279584; 339
Andreas Lutterotti
Andreas Lutterotti
Contributions
Abstract

Abstract: 339

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

A. Lutterotti1, T.H. Ludersdorfer2, M.J. Docampo2, M. Hohmann2, C. Selles Moreno2, H. Hayward-Koennecke2, N. Pfender3, I. Jelcic3, T. Mueller2, C. Blumer4, S. Schippling1, M. Foege2, S. Winklhofer5, R. Stenger2, M. Kayser2, U. Schanz6, M. Sospedra3, R. Martin1

1Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, 2Wyss Zurich, University of Zurich and Federal Institute of Technology (ETH) Zurich, 3Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 4Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, 5University Hospital Zurich, 6Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland

Background: Induction of antigen-specific immune tolerance is the most specific way of correcting a pathogenic immune response to treat autoimmune diseases. We have developed a therapeutic regimen employing autologous blood cells chemically coupled with peptides to induce antigen-specific tolerance in MS. Seven myelin peptides from three different myelin proteins myelin basic protein (MBP83-99, MBP13-32, MBP111-129, MBP146-170), myelin oligodendrocyte glycoprotein (MOG1-20 and MOG35-55) and proteolipid protein (PLP139-154) were previously identified as important target antigens in MS. After a successful trial with myelin peptide coupled PBMC in MS patients (1) we have optimized the approach using red blood cells (RBCs) as tolerogenic carriers.
Methods: A phase Ib clinical trial was performed to test the safety and tolerability of increasing doses of autologous peptide-coupled RBCs. The primary endpoint was safety and tolerability, measured by the number and severity of adverse events (AE), including worsening of MS. The trial consisted of an 8 weeks baseline phase, a 6 weeks core phase and a 6 months safety follow up. Patients underwent regular clinical, brain MRI and laboratory assessments. Sampling for mechanistic studies included blood, CSF and leukapheresis taken before and after treatment. Several immune parameters, including immune cell phenotyping, cytokine production and antigen-specific T cell responses were measured before and after therapy.
Result: Ten relapsing-remitting MS patients (mean age 38.5, female 70%) were treated with increasing doses (patients 1-2: 1x1010, patients 3-5: 1x1011, patients 6-10: 3x1011) of peptide-coupled RBCs. The trial met its primary endpoint, demonstrating feasibility, safety and excellent tolerability. There was no AE within the 24 hours after infusion and no SAE occurred in the trial. Patients remained stable in all clinical parameters. The trial was accompanied by mechanistic studies to assessin-vivoimmunological effects of the therapy. In summary there was a reduction in antigen-specific T cell responses to myelin peptides in the high dose group. Increases in induced regulatory T cells (Tr1), IL10 and natural regulatory T cells (nTreg) point towards active mechanisms of immune tolerance.
Conclusion: In summary, we report the safety and tolerability of a novel antigen-specific therapy for MS patients. Mechanistic studies support active induction of immune tolerance through peptide-coupled RBCs.
Disclosure: The ETIMSred project is supported by the Wyss Zurich Center. Further support has been given by the Clinical Research Priority Project-MS of the University Zurich, ERC Advanced Grant 349733 to R. Martin, and a private donation by SJ.
A. Lutterotti: Received financial compensation and/or travel support for lectures and advice from Biogen, Merck, Novartis, Teva, Genzyme, Bayer, Celgene. A Lutterotti is a co-founder of Cellerys and Co-inventor on a patent held by the University of Zurich on the use of peptide-coupled cells for treatment of MS.
R. Martin: Received unrestricted grants from Biogen and Novartis. Received financial compensation for lectures and advisory tasks from Biogen, Merck, Novartis, Roche, Teva, Genzyme, Neuway and CellProtect. R. Martin is a co-founder/-owner of Cellerys. R. Martin has received royalties for an NIH-held patent on the use of daclizumab in MS.

Abstract: 339

Type: Scientific Session

Abstract Category: Scientific Session 17: Late Breaking News

A. Lutterotti1, T.H. Ludersdorfer2, M.J. Docampo2, M. Hohmann2, C. Selles Moreno2, H. Hayward-Koennecke2, N. Pfender3, I. Jelcic3, T. Mueller2, C. Blumer4, S. Schippling1, M. Foege2, S. Winklhofer5, R. Stenger2, M. Kayser2, U. Schanz6, M. Sospedra3, R. Martin1

1Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich and University of Zurich, 2Wyss Zurich, University of Zurich and Federal Institute of Technology (ETH) Zurich, 3Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University Hospital Zurich, 4Neuroimmunology and Multiple Sclerosis Research Section, Department of Neurology, University of Zurich, 5University Hospital Zurich, 6Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland

Background: Induction of antigen-specific immune tolerance is the most specific way of correcting a pathogenic immune response to treat autoimmune diseases. We have developed a therapeutic regimen employing autologous blood cells chemically coupled with peptides to induce antigen-specific tolerance in MS. Seven myelin peptides from three different myelin proteins myelin basic protein (MBP83-99, MBP13-32, MBP111-129, MBP146-170), myelin oligodendrocyte glycoprotein (MOG1-20 and MOG35-55) and proteolipid protein (PLP139-154) were previously identified as important target antigens in MS. After a successful trial with myelin peptide coupled PBMC in MS patients (1) we have optimized the approach using red blood cells (RBCs) as tolerogenic carriers.
Methods: A phase Ib clinical trial was performed to test the safety and tolerability of increasing doses of autologous peptide-coupled RBCs. The primary endpoint was safety and tolerability, measured by the number and severity of adverse events (AE), including worsening of MS. The trial consisted of an 8 weeks baseline phase, a 6 weeks core phase and a 6 months safety follow up. Patients underwent regular clinical, brain MRI and laboratory assessments. Sampling for mechanistic studies included blood, CSF and leukapheresis taken before and after treatment. Several immune parameters, including immune cell phenotyping, cytokine production and antigen-specific T cell responses were measured before and after therapy.
Result: Ten relapsing-remitting MS patients (mean age 38.5, female 70%) were treated with increasing doses (patients 1-2: 1x1010, patients 3-5: 1x1011, patients 6-10: 3x1011) of peptide-coupled RBCs. The trial met its primary endpoint, demonstrating feasibility, safety and excellent tolerability. There was no AE within the 24 hours after infusion and no SAE occurred in the trial. Patients remained stable in all clinical parameters. The trial was accompanied by mechanistic studies to assessin-vivoimmunological effects of the therapy. In summary there was a reduction in antigen-specific T cell responses to myelin peptides in the high dose group. Increases in induced regulatory T cells (Tr1), IL10 and natural regulatory T cells (nTreg) point towards active mechanisms of immune tolerance.
Conclusion: In summary, we report the safety and tolerability of a novel antigen-specific therapy for MS patients. Mechanistic studies support active induction of immune tolerance through peptide-coupled RBCs.
Disclosure: The ETIMSred project is supported by the Wyss Zurich Center. Further support has been given by the Clinical Research Priority Project-MS of the University Zurich, ERC Advanced Grant 349733 to R. Martin, and a private donation by SJ.
A. Lutterotti: Received financial compensation and/or travel support for lectures and advice from Biogen, Merck, Novartis, Teva, Genzyme, Bayer, Celgene. A Lutterotti is a co-founder of Cellerys and Co-inventor on a patent held by the University of Zurich on the use of peptide-coupled cells for treatment of MS.
R. Martin: Received unrestricted grants from Biogen and Novartis. Received financial compensation for lectures and advisory tasks from Biogen, Merck, Novartis, Roche, Teva, Genzyme, Neuway and CellProtect. R. Martin is a co-founder/-owner of Cellerys. R. Martin has received royalties for an NIH-held patent on the use of daclizumab in MS.

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies