A Phase IIa Study of Vitamin D3 Tolerogenic Dendritic Cells (tolDC) for Multiple Sclerosis

Official title

An Autologous and Antigen-specific Cell-based Therapy of Vitamin D3-treated and Myelin-derived Peptide Loaded Tolerogenic Dendritic Cells in Subjects With Progressive Forms of Multiple Sclerosis: a Phase IIa, Open-label, Self-controlled, Multi-center Clinical Trial

Overview

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.

Detailed description

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.

Interventions

• Biological Tolerogenic dendritic cells (tolDC)
  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

Primary outcome measures

• Efficacy (Change in EDSS score) [Time frame: 62 weeks]
• Incidence of treatment-emergent adverse events (safety and tolerability) [Time frame: 62 weeks]

Secondary outcome measures (6)

• 9 Hole Peg Test (9HPT) [Time frame: 62 weeks]
• Symbol Digit Modalities test (SDMT) [Time frame: 62 weeks]
• T2 lesion volume on MRI [Time frame: 62 weeks]
• Total Brain Volume on MRI [Time frame: 62 weeks]
• Brain Atrophy on MRI [Time frame: 62 weeks]
• Biomarkers [Time frame: 62 weeks]

Eligibility criteria

Inclusion criteria

• 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
• No clinical evidence of relapses in the past 2 years
• Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.
• Appropriate venous access
• Use of adequate contraceptive measures or not of childbearing potential

Exclusion criteria

• 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
• Pregnancy or planning pregnancy in the next 12 months and breast feeding
• Drug or alcohol abuse
• Inability to undergo MRI assessments
• History of or actual signs of immunodeficiency or malignancies (with the exception of treated basal cell carcinoma)
• Concurrent clinically relevant cardiac, immunological, pulmonary, neurological, renal or other major disease that could impact safety or outcome measures.
• Active or chronic infection with hepatitis B, C, HIV, syphilis or tuberculosis
• Splenectomy
• Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity that could interfere with the compliance to the protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Belgium · 1 center

• Universitair Ziekenhuis Antwerpen (UZA) — Edegem

Spain · 1 center

• Germans Trias i Pujol Hospital (HUGTiP) — Badalona

Identifiers

NCT: NCT07020715 · CCRG22-002 / FWO-TBM T002523N · T002523N · 2025-522040-40-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗