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