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.
Patient is ≥ 18 years old, and ≤65 years of age, at time of screening visit
Diagnosis of MS according to the 2017 McDonald Criteria or more recent criteria
Progressive MS by 2014 Lublin MS phenotypic criteria
EDSS 2,0 - ≤7,5
Previous treatment with alemtuzumab, autologous hematopoietic stem cell transplantation or cladribine in the past 3 years.
Prior treatment with any investigational agent within 3 months, or 5 half-lives, whichever is longer.
Current and ongoing treatment with an approved DMT for MS
Treatment with S1P receptor modulators, natalizumab, dimethylfumarate, teriflunomide within the last 3 months prior to study enrolment; last treatment with B cell depleting monoclonal antibodies at least 6 months prior to enrollment and normal CD19 B cell counts at time of enrollment
Single group
Tolerogenic dendritic cells (tolDC)
Biological/VaccineIn 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).
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
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).
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.
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).
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.
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
Immunological response
To comprehensively assess therapy-related immunological changes and the induction of antigen-specific tolerance, we will perform high-dimensional immune profiling using cryopreserved peripheral blood mononuclear cells (PBMCs) and matched serum/plasma samples collected at predefined time points throughout the trial. In brief, we will store samples of PBMC in biobank facilities in Antwerp and Spain prior to vaccination and during and after the IMP administrations for future centralized high-dimensional functional immune-profiling.
Patient Reported Outcomes - Visual Analog Scale (VAS)
Measures pain intensity. The VAS consists of a 10cm line, with two end points representing 0 ('no pain') and 10 ('pain as bad as it could possibly be')
Patient Reported Outcomes - EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L)
The EQ-5D-5L is a self-reported questionnaire designed to assess health-related quality of life. It evaluates five key dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a five-point scale, ranging from no problems to extreme problems (e.g., I have no problems walking about, slight problems, moderate problems, severe problems or I am unable to walk). In addition to these dimensions, the questionnaire includes a VAS, where respondents rate their overall health on a scale from 0 to 100 - 0 representing the worst imaginable health and 100 the best.
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University Hospital, Antwerp
Lead sponsor
Fundació Institut Germans Trias i Pujol
Collaborator
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