The investigators propose to design and conduct a phase IIa clinical trial to treat patients with progressive forms of multiple sclerosis (MS) by vaccination with tolerogenic dendritic cells (tolDC), generated using Good Manufacturing Practices (GMP). Hereby, the investigators want to demonstrate the efficacy and safety of administrating clinical-grade vitamin D3-treated tolDC loaded with myelin-derived peptides to patients with progressive forms of MS. 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.
This is an open-label, self-controlled, multi-center phase IIa clinical trial designed to evaluate the proof-of-concept for both efficacy and safety of tolDC-based therapy. The primary objective is to determine whether treatment with tolDC is effective (using a surrogate primary outcome-change in EDSS score) and safe (the occurrence and severity of adverse events). Secondary evaluations will include the clinical outcomes (assessed using 9HPT, SDMT and number and severity of relapses) and MRI-based markers. Participants will serve as their own controls, with data from 24 weeks pre-treatment period (documented by their neurologist). Following six tolDC administrations, a 24-weeks follow-period will take place. Furthermore, participants can enroll voluntarily into an optional additional follow-up phase of 52 weeks. Completion of screening assessments and confirmation of eligibility criteria should take no longer than 8 weeks.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
In brief, clinical-grade tolDC vaccines will be prepared from leukapheresis starting material of non-mobilized blood and subsequent immunomagnetic selection of CD14+ monocytes using a CliniMACS device. CD14+ monocytes will then be cultured in GMP-grade cell culture medium supplemented with 2% human AB serum, GM-CSF, IL-4 and 1 alpha,25 dihydroxyvitamin D3. At day 4, tolDC will be stimulated using a cytokine cocktail to induce a migratory phenotype. At day 6, tolDC will be harvested, loaded with antigen, resuspended, and cryopreserved. Separate aliquots of the cell product are prepared for final quality control and quality assurance (QC/QA) assessment. This includes cell count, viability, phenotypic analysis using flow cytometry, and induction of T cell hyporesponsiveness in allogeneic mixed leukocyte reaction (allo-MLR).
Universitair Ziekenhuis Antwerpen (UZA)
Edegem, Belgium
Germans Trias i Pujol Hospital (HUGTiP)
Badalona, Spain
Efficacy (Change in EDSS score)
To evaluate the efficacy of tolDC administration, the change in Expanded Disability Severity Scale (EDSS) will be employed. The participants' disability level well be checked during every visit. The EDSS consists of a 10-point scale of disease severity ranging from 0, i.e. no disability, to 10, i.e. death from MS. The impact on disability progression will be analyzed by the proportion of participants free from confirmed disability progression, defined by sustained changes in the EDSS score. Disease progression criteria: * 1.0 point in participants with a screening EDSS of 0-5.0 * 0.5 point in those with a screening EDSS of 5.5-6.0
Time frame: 62 weeks
Incidence of treatment-emergent adverse events (safety and tolerability)
Tolerability and safety of tolDC administration will be assessed by recording the incidence, severity, and relationship to study treatment of adverse events throughout the trial. Participants will be monitored by the treating neurologist for the occurrence and outcomes of AEs, SAEs, relapses and study discontinuations. Full physical examinations, vital signs, and blood and urine samples (only in case of women of childbearing age for pregnancy test) will be recorded at screening, during tolDC administration and during follow-up. An assessment of severity grading of AEs will follow the WHO toxicity grading scale (1= mild, 2= moderate, 3= severe, 4= potentially life threatening).
Time frame: 62 weeks
9 Hole Peg Test (9HPT)
The 9-HPT is a quantitative assessment of upper limb (arm and hand) function. The test device consists of a container containing nine pegs and a wooden or plastic board with nine empty holes. The participant is required to pick up each peg individually and place them as quickly as possible in the nine holes. Once all the pegs are placed in the holes, the participant must remove them one by one, again as quickly as possible and return them to the container. The total time to complete the task is recorded.
Time frame: 62 weeks
Symbol Digit Modalities test (SDMT)
The SDMT is a useful tool for identifying cognitive impairment as well as monitoring changes in cognitive functioning over time or in response to treatment. The SDMT is quick and easy to administer, typically taking about five minutes. The test involves a basic substitution exercise that is easily manageable for adults. Using a reference key, participants are given 90 seconds to match specific numbers with corresponding geometric figures and verbally provide their answers. A study nurse or another appropriately trained individual records the responses in writing. The final outcome is calculated by the total number of answers given minus the incorrect answers (N numbers in 90 seconds).
Time frame: 62 weeks
T2 lesion volume on MRI
T2 lesion volume on MRI scans will be evaluated to determine if administration of tolDC influences clinical and subclinical disease evolution.
Time frame: 62 weeks
Total Brain Volume on MRI
Total brain volume on MRI scans will be evaluated to determine if administration of tolDC influences clinical and subclinical disease evolution
Time frame: 62 weeks
Brain Atrophy on MRI
Atrophy rate on MRI scans will be evaluated to determine if administration of tolDC influences clinical and subclinical disease evolution
Time frame: 62 weeks
Biomarkers
Change in Neurofilament Light Chain (NfL) serum and Glial Fibirallary Acidic Protein (GFAP) serum will be assessed as biomarkers. NfL is a sensitive marker of neuroaxonal damage and has been associated with disease activity and treatment response in MS. GFAP reflects astrocytic activation and may provide insights into neuroinflammation and glial responses, particularly relevant in progressive MS. These biomarkers will be measured using ultrasensitive immunoassays, allowing for high-resolution monitoring of subclinical disease progression and treatment-related effects. These will be measured in serum samples and biobanked for later analysis.
Time frame: 62 weeks
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