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

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

— TOLERVIT-MS  

Official title:

Tolerance-Induction With Dendritic Cells Treated With Vitamin-D3 and Loaded With Myelin Peptides, in Multiple Sclerosis Patients (TOLERVIT-MS)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02903537
• Other study ID #: TOLERVIT-MS
• Secondary ID: 2015-003541-26
• Status: Recruiting
• Phase: Phase 1
• Start date: July 6, 2017
• Est. completion date: December 2023

Study information

• Verified date: July 2023
• Source: Fundació Institut Germans Trias i Pujol
• Contact: Cristina Ramo, MD.PhD. Neurologist
• Phone: +34934978433
• Email: cramot.germanstrias[@]gencat.cat
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Phase I dose ascending ("best of five") clinical trial. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 16
• Est. completion date: December 2023
• Est. primary completion date: December 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

1. EDSS of 0.0 - 6.5.

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:

1. Use of corticosteroids during the prior 4 weeks.

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.

Related Conditions & MeSH terms

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

Intervention

Drug:
• Autologous VitD3 tolerogenic monocyte-derived dendritic cells loaded with a pool of myelin peptides (tolDC-VitD3)
Intranodal administration
• Interferon-beta
Subcutaneous administration interferon-beta

Locations

Country	Name	City	State
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Clínica Universidad de Navarra	Pamplona	Navarra

Sponsors (2)

Lead Sponsor	Collaborator
Fundació Institut Germans Trias i Pujol	Clinica Universidad de Navarra, Universidad de Navarra

Country where clinical trial is conducted

Spain, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety as assessed by the occurrence and severity of adverse events	Occurence and severity of adverse events will be recorded	24 months
Primary	Neurologic changes	New relapse. Disability progression on Expanded Disability Status Scale (EDSS)	24 months
Primary	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	Annual relapse rate (ARR)		24 months
Secondary	Expanded Disability Status Scale (EDSS)		24 months
Secondary	9-Hole Peg Test (9HPT)		24 months
Secondary	25-Foot Walking Test (T25FW)		24 months
Secondary	Symbol Digit Modalities Test (SDMT)		24 months
Secondary	Radiologic preliminary efficacy	Number of new or enlarging T2 lesions on brain MRI. Number of Gadolinium (Gd)-enhancing T1 lesions on brain MRI	24 months
Secondary	Lymphocyte proliferation to myelin peptides		24 months
Secondary	Blood Immunomonitoring studies		24 months
Secondary	Feasibility	Generation of Good Manufacturing Practices (GMP)-grade cell product released according to Quality Control. Feasibility of cellular product injection.	6 months

External Links

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