Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS)
NCT ID: NCT02903537
Last Updated: 2023-07-07
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE1
16 participants
INTERVENTIONAL
2017-07-06
2023-12-31
Brief Summary
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To evaluate the preliminary proof of concept by clinical and/or radiological activity and immunological markers.
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Detailed Description
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First group will start by intranodal injection in cervical lymph nodes of 5\*10\^6 tolDC-VitD3.
Up titration depending on security outcomes to 10\*10\^6 tolDC-VitD3, same route in second cohort dose and next uptitration to 15\*10\^6 tolDC-VitD3.
Six cycles per patient with the following schema: for the first four cycles the administration will be each 2 weeks, for the remaining 2 cycles administration each 4 weeks.
A last cohort with the dose identified in the previous groups, administered in patients treated with beta interferon, same route, same dose schema.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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5 * 10 ^6 tolDC-VitD3
5 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
10 * 10 ^6 tolDC-VitD3
10 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).
Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
15 * 10 ^6 tolDC-VitD3
15 million autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3).
Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Interferon-beta
Additional group (patients treated with beta-interferon) will receive the selected dose of those 3 previously cohorts studied
Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Interferon-beta
Subcutaneous administration interferon-beta
Interventions
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Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
Interferon-beta
Subcutaneous administration interferon-beta
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Multiple Sclerosis according to 2010 revised Mc Donald criteria, and less than 15 years of evolution of disease.
3. 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)
4. 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).
5. Adequate peripheral venous access.
6. Signed informed consent.
Exclusion Criteria
2. Use of interferon beta -in patients who is retired by inefficiency or other causes- and glatiramer acetate in the 4 weeks prior.
3. Use of fingolimod, dimethylfumarate, natalizumab, immunoglobulins or plasmapheresis at 12 weeks; and teriflunomide in the 15 weeks prior.
4. Use of azathioprine, mitoxantrone, rituximab, methotrexate, cyclophosphamide, cyclosporine, alemtuzumab or other immunosuppressive drug, except corticosteroids, at any time.
5. Bone marrow or stem cell transplant at any time.
6. 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.
7. Pregnancy or planning pregnancy within the next 12 months and breastfeeding.
8. 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.
9. Abusing drugs or alcohol.
10. Inability to undergo MRI evaluations.
11. Seropositivity for HIV, hepatitis B or C and/or syphilis.
12. History of oncological disease.
13. Clinically relevant concomitant disease: cardiac, pulmonary, neurological, renal or other major illness.
14. Splenectomy.
15. Dementia, psychiatric problems or other comorbidities that might interfere protocol compliance.
16. To be participating in another clinical study or to have participated in one in the last 3 months.
18 Years
60 Years
ALL
No
Sponsors
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Clinica Universidad de Navarra, Universidad de Navarra
OTHER
Fundació Institut Germans Trias i Pujol
OTHER
Responsible Party
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Principal Investigators
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Cristina Ramo, MD.PhD.Neurologist
Role: PRINCIPAL_INVESTIGATOR
Badalona Hospital Germans Trias i Pujol. Neurology service. Multiple Sclerosis department
Eva Martínez-Cáceres, MD.PhD.Immunology
Role: STUDY_DIRECTOR
Badalona Hospital Germans Trias i Pujol. Immunology
Locations
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Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Clínica Universidad de Navarra
Pamplona, Navarre, Spain
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Related Links
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European Cooperation in Science and Technology (COST), Action BM1305 "Action to focus and accelerate cell-based tolerogenic therapies"
Other Identifiers
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2015-003541-26
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
TOLERVIT-MS
Identifier Type: -
Identifier Source: org_study_id
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