Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis

NCT ID: NCT05251870

Last Updated: 2022-02-23

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-08-17
• Study Completion Date: 2025-08-31

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intranodal TolDCB29 (low dose)

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Intranodal TolDCB29 (intermediate dose)

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Intranodal TolDCB29 (high dose)

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Intranodal TolDCB29 (recommended dose)

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.

Group Type: EXPERIMENTAL

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

Intervention Type: DRUG

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

Interventions

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

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

Intervention Type: DRUG

Other Intervention Names

TolDCB29

Eligibility Criteria

Inclusion Criteria

• 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)

Exclusion Criteria

• 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

• Intramuscular or intra-articular glucocorticoid injection during 12 weeks prior to inclusion
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Radboud University Medical Center

OTHER

Sponsor Role: collaborator

Utrecht University

OTHER

Sponsor Role: collaborator

Trajectum Pharma B.V.

UNKNOWN

Sponsor Role: collaborator

Dutch Arthritis Association

INDUSTRY

Sponsor Role: collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role: collaborator

Health Holland

OTHER

Sponsor Role: collaborator

UMC Utrecht

OTHER

Sponsor Role: lead

Responsible Party

Jacob M van Laar

Professor of Rheumatology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jacob M van Laar, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Arie J Stoppelenburg, PhD

Role: STUDY_DIRECTOR

UMC Utrecht

Locations

Radboud University Medical Centre

Nijmegen, , Netherlands

Site Status: ACTIVE_NOT_RECRUITING

University Medical Centre Utrecht

Utrecht, , Netherlands

Site Status: RECRUITING

Utrecht University

Utrecht, , Netherlands

Site Status: ACTIVE_NOT_RECRUITING

Countries

Netherlands

Central Contacts

Arie J Stoppelenburg, PhD

Role: CONTACT

a.j.stoppelenburg@umcutrecht.nl

+31302535589

Research nurses

Role: CONTACT

tolerant@umcutrecht.nl

References

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.

Reference Type: DERIVED

PMID: 39266308 (View on PubMed)

Other Identifiers

2019-003620-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL71296.000.20

Identifier Type: -

Identifier Source: org_study_id