Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS)

NCT02903537 | Unknown Phase 1 DMC

• 2 other identifiers: TOLERVIT-MS2015-003541-26
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to determine the safety and tolerability of the intranodal administration of autologous monocyte-derived dendritic cells tolerised with Vitamin-D3 and pulsed with myelin peptides (tolDC-VitD3) in multiple sclerosis patients . To select the most appropriate regime for the development of future therapeutic trials. To evaluate the preliminary proof of concept by clinical and/or radiological activity and immunological markers.

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive

Keywords

Multiple Sclerosis; Dendritic Cells; Immune Tolerance; Myelin Proteins; Tolerogenic dendritic cells

Outcome Measures

Primary Outcomes (3)

• Safety as assessed by the occurrence and severity of adverse events

  Occurence and severity of adverse events will be recorded

  24 months

• Neurologic changes

  New relapse. Disability progression on Expanded Disability Status Scale (EDSS)

  24 months

• Radiologic changes

  Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI

  24 months

Secondary Outcomes (9)

• Annual relapse rate (ARR)

  24 months

• Expanded Disability Status Scale (EDSS)

  24 months

• 9-Hole Peg Test (9HPT)

  24 months

• 25-Foot Walking Test (T25FW)

  24 months

• Symbol Digit Modalities Test (SDMT)

  24 months

Study Arms (4)

5 * 10 ^6 tolDC-VitD3

EXPERIMENTAL

5 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

10 * 10 ^6 tolDC-VitD3

EXPERIMENTAL

10 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

15 * 10 ^6 tolDC-VitD3

EXPERIMENTAL

15 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).

Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)

Interferon-beta

EXPERIMENTAL

Additional group (patients treated with beta-interferon) will receive the selected dose of those 3 previously cohorts studied

Drug: Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3); Drug: Interferon-beta

Interventions

Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3) DRUG

Intranodal administration

Also known as: tolDC-VitD3

10 * 10 ^6 tolDC-VitD3; 15 * 10 ^6 tolDC-VitD3; 5 * 10 ^6 tolDC-VitD3; Interferon-beta

Interferon-beta DRUG

Subcutaneous administration interferon-beta

Also known as: beta-interferon

Interferon-beta

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• EDSS of 0.0 - 6.5.
• Multiple Sclerosis according to 2010 revised Mc Donald criteria, and less than 15 years of evolution of disease.
• Patients with:
• Active relapsing remitting multiple sclerosis (RRMS) (more than 1 relapse in last year and/or occurrence of ≥3 new T2 lesions or Gd positive) who not wish to be treated with current therapies.
• Low activity RRMS (1 relapse in last year or occurrence of 1 or 2 T2 lesions or Gd positive) without treatment.
• Progressive forms of MS with activity (at least 1 relapse in last year or occurrence 1 or 2 T2 lesions or Gd positive).
• RRMS treated with interferon beta (Additional group)
• T cell proliferation to the pool of myelin peptides against which is to induce immune tolerance: Myelin basic protein (MBP)13-32, MBP83-99, MBP111-129, MBP146-170, proteolipid protein (PLP) 139-154, Myelin oligodendrocyte glycoprotein (MOG)1-20, MOG35 -55).
• Adequate peripheral venous access.
• Signed informed consent.

You may not qualify if:

• Use of corticosteroids during the prior 4 weeks.
• Use of interferon beta -in patients who is retired by inefficiency or other causes- and glatiramer acetate in the 4 weeks prior.
• Use of fingolimod, dimethylfumarate, natalizumab, immunoglobulins or plasmapheresis at 12 weeks; and teriflunomide in the 15 weeks prior.
• Use of azathioprine, mitoxantrone, rituximab, methotrexate, cyclophosphamide, cyclosporine, alemtuzumab or other immunosuppressive drug, except corticosteroids, at any time.
• Bone marrow or stem cell transplant at any time.
• Relapse during the month prior of starting treatment. If it appears and the patient meets the eligibility criteria, must wait long enough until the end of the 30 days free of relapse. If corticosteroids are administered, the MRI performed during this period should not be considered, and a new MRI will be performed at 4 weeks after administration of corticosteroids.
• Pregnancy or planning pregnancy within the next 12 months and breastfeeding.
• Fertile patients who are not using an appropriate method of contraception. If the patient is menopausal or sterile it must be documented in the medical record.
• Abusing drugs or alcohol.
• Inability to undergo MRI evaluations.
• Seropositivity for HIV, hepatitis B or C and/or syphilis.
• History of oncological disease.
• Clinically relevant concomitant disease: cardiac, pulmonary, neurological, renal or other major illness.
• Splenectomy.
• Dementia, psychiatric problems or other comorbidities that might interfere protocol compliance.

Sponsors & Collaborators

• Fundació Institut Germans Trias i Pujol: lead
• Clinica Universidad de Navarra, Universidad de Navarra: collaborator

Study Sites (2)

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

RECRUITING

Clínica Universidad de Navarra

Pamplona, Navarre, 31008, Spain

NOT YET RECRUITING

Related Publications (11)

• Lutterotti A, Yousef S, Sputtek A, Sturner KH, Stellmann JP, Breiden P, Reinhardt S, Schulze C, Bester M, Heesen C, Schippling S, Miller SD, Sospedra M, Martin R. Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. Sci Transl Med. 2013 Jun 5;5(188):188ra75. doi: 10.1126/scitranslmed.3006168.

  PMID: 23740901 BACKGROUND

• Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011 Sep;34(9):2026-32. doi: 10.2337/dc11-0472. Epub 2011 Jun 16.

  PMID: 21680720 BACKGROUND

• Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, Pahau H, Lee BT, Ng J, Brunck ME, Hyde C, Trouw LA, Dudek NL, Purcell AW, O'Sullivan BJ, Connolly JE, Paul SK, Le Cao KA, Thomas R. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med. 2015 Jun 3;7(290):290ra87. doi: 10.1126/scitranslmed.aaa9301.

  PMID: 26041704 BACKGROUND

• Naranjo-Gomez M, Raich-Regue D, Onate C, Grau-Lopez L, Ramo-Tello C, Pujol-Borrell R, Martinez-Caceres E, Borras FE. Comparative study of clinical grade human tolerogenic dendritic cells. J Transl Med. 2011 Jun 9;9:89. doi: 10.1186/1479-5876-9-89.

  PMID: 21658226 BACKGROUND

• Raiotach-Regue D, Grau-Lopez L, Naranjo-Gomez M, Ramo-Tello C, Pujol-Borrell R, Martinez-Caceres E, Borras FE. Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. Eur J Immunol. 2012 Mar;42(3):771-82. doi: 10.1002/eji.201141835.

  PMID: 22488365 BACKGROUND

• Mansilla MJ, Selles-Moreno C, Fabregas-Puig S, Amoedo J, Navarro-Barriuso J, Teniente-Serra A, Grau-Lopez L, Ramo-Tello C, Martinez-Caceres EM. Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis. CNS Neurosci Ther. 2015 Mar;21(3):222-30. doi: 10.1111/cns.12342. Epub 2014 Nov 18.

  PMID: 25403984 BACKGROUND

• Raich-Regue D, Naranjo-Gomez M, Grau-Lopez L, Ramo C, Pujol-Borrell R, Martinez-Caceres E, Borras FE. Differential effects of monophosphoryl lipid A and cytokine cocktail as maturation stimuli of immunogenic and tolerogenic dendritic cells for immunotherapy. Vaccine. 2012 Jan 5;30(2):378-87. doi: 10.1016/j.vaccine.2011.10.081. Epub 2011 Nov 12.

  PMID: 22085546 BACKGROUND

• Ten Brinke A, Hilkens CM, Cools N, Geissler EK, Hutchinson JA, Lombardi G, Lord P, Sawitzki B, Trzonkowski P, Van Ham SM, Martinez-Caceres EM. Clinical Use of Tolerogenic Dendritic Cells-Harmonization Approach in European Collaborative Effort. Mediators Inflamm. 2015;2015:471719. doi: 10.1155/2015/471719. Epub 2015 Dec 24.

  PMID: 26819498 BACKGROUND

• Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, Fouweather T, MacDonald C, Chadwick T, McColl E, Dunn J, Dickinson AM, Hilkens CM, Isaacs JD. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2017 Jan;76(1):227-234. doi: 10.1136/annrheumdis-2015-208456. Epub 2016 Apr 26.

  PMID: 27117700 BACKGROUND

• Mansilla MJ, Contreras-Cardone R, Navarro-Barriuso J, Cools N, Berneman Z, Ramo-Tello C, Martinez-Caceres EM. Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients. J Neuroinflammation. 2016 May 20;13(1):113. doi: 10.1186/s12974-016-0584-9.

  PMID: 27207486 BACKGROUND

• Willekens B, Presas-Rodriguez S, Mansilla MJ, Derdelinckx J, Lee WP, Nijs G, De Laere M, Wens I, Cras P, Parizel P, Van Hecke W, Ribbens A, Billiet T, Adams G, Couttenye MM, Navarro-Barriuso J, Teniente-Serra A, Quirant-Sanchez B, Lopez-Diaz de Cerio A, Inoges S, Prosper F, Kip A, Verheij H, Gross CC, Wiendl H, Van Ham MS, Ten Brinke A, Barriocanal AM, Massuet-Vilamajo A, Hens N, Berneman Z, Martinez-Caceres E, Cools N, Ramo-Tello C; RESTORE consortium. Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration. BMJ Open. 2019 Sep 9;9(9):e030309. doi: 10.1136/bmjopen-2019-030309.

  PMID: 31501122 DERIVED

Related Links

• European Cooperation in Science and Technology (COST), Action BM1305 "Action to focus and accelerate cell-based tolerogenic therapies"

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis

Interventions

Interferon-beta

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Cristina Ramo, MD.PhD.Neurologist

  Badalona Hospital Germans Trias i Pujol. Neurology service. Multiple Sclerosis department

  PRINCIPAL INVESTIGATOR

• Eva Martínez-Cáceres, MD.PhD.Immunology

  Badalona Hospital Germans Trias i Pujol. Immunology

  STUDY DIRECTOR

Central Study Contacts

Cristina Ramo, MD.PhD. Neurologist

CONTACT

+34934978433; cramot.germanstrias@gencat.cat

Ana M Barriocanal, MD.PhD.Clinical Pharmacologist

CONTACT

+34934978488; ambarrioocanal@igtp.cat

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2016
• First Posted: September 16, 2016
• Study Start: July 6, 2017
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: July 7, 2023

Record last verified: 2023-07

Locations

ES (2)