Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis

NCT05251870 | Unknown Phase 1 DMC

• 2 other identifiers: NL71296.000.202019-003620-20
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

Rationale: In rheumatoid arthritis, immune cells cause joint inflammation and destruction in response to autoantigens. Immunosuppressive therapies offer relief but fail to induce tolerance to autoantigens. Injection of antigen-loaded tolerogenic dendritic cells induces immune tolerance and ameliorates disease in arthritis models. The investigators hypothesize that dendritic cell therapy with TolDCB29 is safe and induces immune tolerance in rheumatoid arthritis patients. Objective: The aim of the study is to demonstrate the safety and feasibility of intranodal TolDCB29 administration. Secondary objectives are the characterization of B29-peptide specific immune reactivity in response to TolDCB29 treatment and the evaluation of the effect of the treatment on disease activity. Study design: Phase I/II, open-label, dose-escalation clinical trial. Study population: Adult patients (\>18 years) with rheumatoid arthritis in remission or low disease activity while on disease modifying anti-rheumatic drugs (DMARD) will be included. Any combination and dose of DMARD is allowed, with exception of Janus kinase inhibitors. Concomitant use of a low dose of prednisone (7.5 mg per day or below) is allowed. Medication should be stable for at least twelve weeks. 18 patients will undergo the experimental treatment. Intervention: Study participants will receive two intranodal injections with the TolDCB29 product with a four-week interval. During the first phase of the study dose escalation is performed, in which the first group (n=3) receives two "low dose" injections, the second group (n=3) receives two "intermediate dose" injections, and the third group (n=3) receives two "high dose" injections. During the second phase, a fourth group (n=9) will receive the highest dosage without attributable serious adverse events thus far.

Conditions

Rheumatoid Arthritis

Keywords

Tolerogenic Dendritic Cells

Outcome Measures

Primary Outcomes (3)

• Safety as assessed by the occurrence and severity of adverse events

  The occurrence and severity of adverse events will be recorded, including the occurrence of disease flares.

  34 weeks

• Quantity of good manufacturing practices (GMP)-grade TolDCB29 released according to Quality Control.

  Number of TolDCB29 cells (millions of cells) per patient that were released according to the quality control standards of the IMPD.

  34 weeks

• Occurrence of out of specification (OOS) products.

  Number of occurrences that out of specification TolDCB29 products were generated during manufacturing and/or reconsitution.

  34 weeks

Secondary Outcomes (3)

• Changes in leukocyte numbers

  34 weeks

• Changes in CD4+ T lymphocytes subset frequencies

  34 weeks

• Lymphocyte proliferation to HSP70/B29 peptide

  34 weeks

Other Outcomes (4)

• Disease activity of 28 joints (DAS28)

  34 weeks

• Quality of life (EQ-5D-5L)

  34 weeks

• Mean functional ability (HAQ)

  34 weeks

Study Arms (4)

Intranodal TolDCB29 (low dose)

EXPERIMENTAL

Two administrations of 5 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Drug: autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70

Intranodal TolDCB29 (intermediate dose)

EXPERIMENTAL

Two administrations of 10 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Drug: autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70

Intranodal TolDCB29 (high dose)

EXPERIMENTAL

Two administrations of 15 million autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). This cohort will consist of three patients.

Drug: autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70

Intranodal TolDCB29 (recommended dose)

EXPERIMENTAL

Two administrations of the recommended dose of autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 (TolDCB29). The recommended dose will be advised by the data safety monitoring board after data review of the first three arms. This cohort will consist of nine patients.

Drug: autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70

Interventions

autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70 DRUG

Intranodal administration into an inguinal lymphnode. Two administrations at the same injection site with a four week interval.

Also known as: TolDCB29

Intranodal TolDCB29 (high dose); Intranodal TolDCB29 (intermediate dose); Intranodal TolDCB29 (low dose); Intranodal TolDCB29 (recommended dose)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of rheumatoid arthritis (RA) according to the criteria which were valid at time of diagnosis (i.e. 1987 Rheumatoid Arthritis Classification or 2010 American College of Rheumatology/EULAR RA Classification Criteria)

You may not qualify if:

• Disease in remission or in low disease activity for at least 12 weeks (disease activity score of 28 joints \< 3.2)
• Able and willing to give informed consent and to comply with the study protocol
• Use of JAK inhibitors
• Active or chronic infection (except fungal nail infection)
• Infection requiring hospitalization or IV antibiotics within 6 weeks of baseline
• Immunization with live vaccine within 6 weeks of baseline
• History of malignancy (except treated basal cell carcinoma of skin)
• Use of other investigational medicinal products within 30 days prior to study entry
• Major surgery within 8 weeks of baseline or planned within 12 weeks from baseline
• Pregnancy, or women planning to become pregnant within the study period, or women who are breast feeding
• Hb\<6 mmol/L; neutrophils\< 2.00 x10\^9/L; platelets \<150x10\^9/L; alanine aminotransferase or alkaline phosphatase\>2x upper limit of normal; renal insufficiency (clearance \< 60 ml/min) at screening visit
• Poor venous access or medical condition precluding leukapheresis
• Serious or unstable co-morbidity deemed unsuitable by PI, e.g. chronic obstructive pulmonary disease, cardiac failure
• Individuals of child bearing potential unwilling to use adequate contraception for duration the of study

Sponsors & Collaborators

• UMC Utrecht: lead
• Radboud University Medical Center: collaborator
• Utrecht University: collaborator
• Trajectum Pharma B.V.: collaborator
• Dutch Arthritis Association: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Health Holland: collaborator

Study Sites (3)

Radboud University Medical Centre

Nijmegen, Netherlands

ACTIVE NOT RECRUITING

University Medical Centre Utrecht

Utrecht, Netherlands

RECRUITING

Utrecht University

Utrecht, Netherlands

ACTIVE NOT RECRUITING

Related Publications (1)

• Stoppelenburg AJ, Schreibelt G, Koeneman B, Welsing P, Breman EJ, Lammers L, de Goede A, Duiveman-de Boer T, van Eden W, Leufkens P, de Vries IJM, Broere F, van Laar JM. Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis. BMJ Open. 2024 Sep 12;14(9):e078231. doi: 10.1136/bmjopen-2023-078231.

  PMID: 39266308 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Jacob M van Laar, MD, PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• Arie J Stoppelenburg, PhD

  UMC Utrecht

  STUDY DIRECTOR

Central Study Contacts

Arie J Stoppelenburg, PhD

CONTACT

+31302535589; a.j.stoppelenburg@umcutrecht.nl

Research nurses

CONTACT

tolerant@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Rheumatology

Study Record Dates

• First Submitted: December 21, 2021
• First Posted: February 23, 2022
• Study Start: August 17, 2021
• Primary Completion: August 1, 2024
• Study Completion: August 1, 2025
• Last Updated: February 23, 2022

Record last verified: 2022-02

Locations

NL (3)