T Cell Vaccination in Patients With Progressive Multiple Sclerosis

Autologous T Cell Vaccination With Line Specific for 9 Myelin Peptides in Patients With Progressive / Relapsing Multiple Sclerosis

This is a double blind phase I-II clinical trial with multiple autologous T cell vaccinations using T cell lines reactive to 9 different myelin peptides of MBP, MOG and PLP, in patients with relapsing progressive Multiple Sclerosis.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Biological: T cell vaccination; Biological: multiple (4 autologous subcutaneous T cell vaccinations with T cell lines reactive to nine myelin peptides)

Detailed Description

This trial is a phase I/II double-blind controlled clinical trial designed to evaluate the safety and clinical efficacy of multiple autologous T-cell vaccinations (on days 1, 30, 90 and 180) in progressive MS patients which showed severe progression/deterioration in the functional status (at least, one degree in the EDSS scale) during the last year, or at least one severe relapse. The patients will be from our MS clinic and will be randomized (by computer) into two groups according to: age, disease duration, disease severity and progression rate. One group (2/3 of the patients) will receive the active treatment, i.e. TCV, and the other group (1/3 of the patients) will receive sham treatment (injection of sterile normal saline). The treating nurse, the treating physician, the examining neurologist (the one who will perform the neurological evaluation) and the patient will be blinded for the treatment.

OBJECTIVES AND SIGNIFICANCE OF THE TRIAL

A. To develop a new cell therapeutic modality for treating MS patients using attenuated autologous anti-MBP, anti-PLP and anti-MOG autoreactive T-cells as vaccines. The immune response induced by this vaccination will be directed specifically against the T-cells attacking the patient's nerve system (specifically the myelin sheath).

B. To study and characterize these autoreactive T-cells in MS patients. The number and function of such cells in the course of the relapse of the disease, as well as during the periods of remissions, will be studied.

C. To study the clinical efficacy of T-cell vaccination with attenuated anti-MBP and anti-MOG autologous T-cells on MS. The parameters to be examined will include: change in the disability status (by the EDSS disability scale, as well as by ambulation index and several other functional tests), the change in the relapse rate and in the timed 10-meters walking test, the PASAT test and the 9-hole peg test. MRI parameters will represent additional endpoints and will include: the changes in the total burden of the disease and in the quantity of irreversible damage (cortical atrophy and axonal loss). In addition, the effects of this treatment on the immune responses (i.e. number and proportion of activated lymphocytes, number and proportion of anti-myelin reactive lymphocytes in the peripheral blood and IgG antibody levels in the cerebrospinal fluid) will be evaluated in the treated MS patients.

The significance and importance of the study are outlined as follows:

1. It offers a new approach for the treatment of MS.
2. This approach has the advantage of being devoid of toxic or general immunosuppressive effects.
3. The study will pave the way for further studies that will improve our understanding of the mechanisms of the host immune response in MS and of the involvement of the MBP, PLP and MOG myelin proteins in the initiation of the auto-reactive immune response and of clinical MS.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel, 91120
    • Dept of Neurology,Hadassah ein-Kerem

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Clinically definite MS (according to Poser's criteria) of the relapsing-progressive type (RPMS).
2. Age: 18-60.
3. EDSS: 3.0 to 7.0.
4. Disease duration: > 1 year.
5. Evidence of disease progression of 1 degree in the EDSS scale, or at least two severe relapses (requiring hospitalization and treatment) during the year prior to inclusion.
6. MRI of the brain with at least 5 lesions in the white matter (T2 imaging).
7. Failure to benefit from other existing treatments according to the guidelines of the Israeli Ministry of Health.

Exclusion Criteria:

1. Patients with other systemic active disease.
2. Patients who had been treated with immunosuppressive drugs during the 3-6 months depending on the cytotoxicity of the medication used prior to the inclusion.
3. Patients who previously received cellular immunotherapy or who are participating in other experimental protocols.
4. Pregnancy; Pregnant women or women who do not use efficacious contraception (oral contraception, or intra-uterine device).
5. Patients with an additional autoimmune condition unrelated to MS or significant allergy.
6. Patients who cannot fully understand the treatment protocol or are unable to sign the informed consent, or in whom the clinician believes that a follow-up period of at least 12 months will not be possible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TCV; multiple T cell vaccinations against nine myelin peptides at days 1, 30, 90, 180	Biological: T cell vaccination; Multiple injections of autologous T cell lines reactive to 9 myelin peptides.
Sham Comparator: Placebo; saline injections subcutaneously at the same 4 time points with active treatment	Biological: multiple (4 autologous subcutaneous T cell vaccinations with T cell lines reactive to nine myelin peptides); multiple (4 autologous subcutaneous T cell vaccinations with T cell lines reactive to nine myelin peptides at days 1, 30,90,180; Other Names: multiple subcutenous injections of saline at days 1, 30,90,180.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EDSS changes	Follow up in changes in the EDSS score	one year
Relapse rate of MS	recording of the relapses of MS during the year of the study and the prior to the study	one year follow up
PASAT test	recording of the performance in the PASAT test during the one year of the study	one year
Nine hole PEG test	recording of the performance in the Nine hole PEG test test during the one year of the study	one year
timed ten meter walking	recording of the performance in the timed ten meter walking test during the one year of the study	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative MRI evaluation	the burden of T2 lesions load, of the hypo-intense T1 lesions, of the Gadolinium enhancing lesions and of the brain atrophy will be evaluated at the end of the study and compared to the baseline values	one year

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization
• Investigators: Principal Investigator: Dimitrios Karussis, Prof., Hadassah Medical Organizatin; Study Director: Rivka Abulafia-Lapid, PhD, Hadassah Medical Organization

Publications and helpful links

General Publications

• Karussis D, Shor H, Yachnin J, Lanxner N, Amiel M, Baruch K, Keren-Zur Y, Haviv O, Filippi M, Petrou P, Hajag S, Vourka-Karussis U, Vaknin-Dembinsky A, Khoury S, Abramsky O, Atlan H, Cohen IR, Abulafia-Lapid R. T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial. PLoS One. 2012;7(12):e50478. doi: 10.1371/journal.pone.0050478. Epub 2012 Dec 14.

Study record dates

Study Major Dates

• Study Start: May 1, 2002
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: October 5, 2011
• First Submitted That Met QC Criteria: October 6, 2011
• First Posted (Estimate): October 7, 2011

Study Record Updates

• Last Update Posted (Estimate): October 7, 2011
• Last Update Submitted That Met QC Criteria: October 6, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: safety; Immunotherapy; Tolerance; clinical efficacy; T cell vaccination
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: TCV-HMO-CTIL; 27-15.15.00 (Other Identifier: Hmo)