A Clinical Trial Evaluating the Safety and Efficacy of Myelin-peptide Loaded tolDC as Treatment for MS

A Controlled Phase II Clinical Trial Evaluating the Safety and Efficacy of Myelin-peptide Loaded tolDC as Treatment for Multiple Sclerosis

The investigators propose to design and conduct a phase II clinical trial to treat patients with multiple sclerosis (MS) by vaccination with tolerogenic dendtritic cells (tolDC), generated using Good Manufacturing Practices (GMP). Hereby, the investigators want to demonstrate the efficacy of administrating clinical-grade vitamin D3-treated tolDC loaded with myelin-derived peptides to treat a well-defined population of MS patients. In vitro generation of dedicated and stable immunomodulatory DC followed by in vitro loading of antigens to ensure tolerance and safety of DC-directed therapy is a promising strategy with the potential to induce long term tolerance

A two-arm non-randomized controlled phase II clinical trial will be conducted in a coordinated and comprehensive manner to provide proof-of-concept for efficacy and safety. The primary objective of the phase II study is to determine whether tolDC-based therapy is effective and safe based on a surrogate outcome measure as primary outcome (i.e. brain MRI). Adverse events, clinical relapse rates, neurological disability (assessed using various scales) and MRI endpoints will be followed and measured over the course of 18 months. Participants who receive the tolDC treatment will be compared to MS patients, who receive standard-of-care (control group). Completion of screening assessments and confirmation of eligibility criteria should take no longer than 8 weeks. Furthermore, patients for the two arms will be recruited simultaneously and at the same pace.

Inclusion Criteria:

• RIS, CIS or MS according to most recent Mc Donald's diagnostic criteria (1);
• Age 18-60 years;
• Expanded disability status scale (EDSS) of 0-6.0 inclusive;
• Active RIS, CIS, MS (relapsing and progressive forms): 1 relapse in the past year and/or at least 1 enhancing lesion on brain MRI in the past year and/or at least 1 new or enlarging T2 lesion in comparison with a reference scan from maximum 1 year before;
• RIS, CIS, MS patients already on first-line treatment or who will start first-line treatment (control arm)
• Untreated patients who do not want to be treated with currently available disease-modifying treatments or presence of treatment-related side effects; intervention arm;
• No evidence of relapse in the month prior to start of screening and throughout the screening phase;
• Only for the intervention arm: Normal total lymphocyte count above 800/mm3;
• Only for the intervention arm: Normal peripheral B cell count between 0.07x106 cells/ml and 0.53x106 cells/mL;
• Able to sign informed consent;
• Ability to comply with the protocol assessments;
• Appropriate venous access;
• Use of adequate contraceptive measures during the duration of the trial. Women and men of reproductive potential can only be included in the study following use of adequate contraceptive measures. Accepted methods of contraception include use of hormonal contraceptives (oral, intravaginal, intrauterine, or transdermal), intrauterine devices, sterilization or postmenopausal status, use of condoms with spermicide.

Exclusion Criteria:

For tolDC intradermal arm:

• Previous use of severe immunosuppressive or cytostatic treatment, including cyclophosphamide, mitoxantrone, bone marrow transplantation or (hematopoietic or mesenchymal) stem cell transplantation (at any time) prior to enrolment;
• Previous use of cladribine with last course within last 2 years or alemtuzumab with last course within last 4 years; lymphocyte counts should be above 800/mm3
• Only for the intervention arm: Use of interferon beta and glatiramer acetate in the 4 previous weeks; use of teriflunomide in the previous 4 weeks with accelerated elimination procedure; use of dimethyl/diroximel fumarate in the previous 4 weeks with normal lymphocyte counts (above 800/mm3)
• Only for the intervention arm: Treatment with fingolimod, siponimod, ponesimod, ozanimod, natalizumab, intravenous or subcutaneous immunoglobulins or plasmapheresis in the past 3 months; teriflunomide in the previous 15 weeks without accelerated elimination; anti-CD20 monoclonal antibody (including ofatumumab, rituximab and ocrelizumab) within the past 6 months prior to the first administration and until confirmation of B cell count normalization; for S1P modulators lymphocyte counts should be above 800/mm3
• Use of another investigational product in the past 6 months or longer depending on the mode of action
• Previous use of azathioprine or methotrexate in the past 3 months; lymphocyte counts should be above 800/mm3
• Previous use of other immunosuppressive agents washout is at least 3 months or longer depending on the mode of action and half-life; lymphocyte counts should be above 800/mm3

For intradermal and control arm:

• Relapse / use of corticosteroids for any reason in the previous month;
• Pregnancy or planning pregnancy in the next 18 months and breast feeding;
• Fertile patients, both men and women, who are not using an adequate method of contraception. If the patient is menopausal or sterile, it must be documented in the medical history;
• Drug or alcohol abuse;
• Inability to undergo MRI assessments or unwillingness to receive gadolinium administration;
• History of or actual signs of immunodeficiency (with the exception of treatment effects of patients on 1st line DMT) or malignancies;
• History of oncological diseases, with the exception of completely removed local basal cell carcinoma
• Concurrent clinically relevant cardiac, immunological, pulmonary, neurological, renal or other major disease;
• Positive hepatitis B or C, HIV serology, syphilis or tuberculosis indicating an active of chronic infection;
• Splenectomy;
• Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity that could interfere with the compliance to the protocol;
• Participating in another interventional clinical trial, assessing an IMP, or having participated in one, in the last 6 months.
• Previous treatment in the phase I clinical trial with tolDC.