Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis (TOLERANT)

Tolerogenic Dendritic Cell Therapy for Rheumatoid Arthritis: the TOLERANT Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: autologous mature tolerogenic monocyte-derived Dendritic Cells loaded with the B29 peptide of HSP70

• Study Type: Interventional
• Enrollment (Anticipated): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Arie J Stoppelenburg, PhD; Phone Number: +31302535589; Email: a.j.stoppelenburg@umcutrecht.nl
• Study Contact Backup: Name: Research nurses; Email: tolerant@umcutrecht.nl

Study Locations

• Netherlands
  • Nijmegen, Netherlands
    • Active, not recruiting
    • Radboud University Medical Centre
  • Utrecht, Netherlands
    • Recruiting
    • University Medical Centre Utrecht
  • Utrecht, Netherlands
    • Active, not recruiting
    • Utrecht University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)
• Stable dose, for at least 12 weeks, of any combination of disease-modifying antirheumatic drugs and glucocorticoids (maximum of 7.5 mg per day), with exception of those drugs that are part of the 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: TolDCB29
Experimental: 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.	Drug: 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.; Other Names: TolDCB29
Experimental: 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.	Drug: 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.; Other Names: TolDCB29
Experimental: 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.	Drug: 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.; Other Names: TolDCB29

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
Changes in leukocyte numbers	34 weeks
Changes in CD4+ T lymphocytes subset frequencies	34 weeks
Lymphocyte proliferation to HSP70/B29 peptide	34 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease activity of 28 joints (DAS28)	Score ranges 0 - 9.4. Higher score means higher disease activity	34 weeks
Quality of life (EQ-5D-5L)	Score ranges from less than 0 to 1. In this score, 0 represents a health state equivalent to death and 1 represents full health.	34 weeks
Mean functional ability (HAQ)	Score ranges 0 - 3.0 in 0.1 increments. Higher scores indicate worse function and greater disability.	34 weeks
Autoantibody levels	Blood autoantibody levels in Units/mL	34 weeks

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Radboud University Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Dutch Arthritis Association; Utrecht University; Health Holland; Trajectum Pharma B.V.
• Investigators: Principal Investigator: Jacob M van Laar, MD, PhD, UMC Utrecht; Study Director: Arie J Stoppelenburg, PhD, UMC Utrecht

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2021
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: December 21, 2021
• First Submitted That Met QC Criteria: February 22, 2022
• First Posted (Actual): February 23, 2022

Study Record Updates

• Last Update Posted (Actual): February 23, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Tolerogenic Dendritic Cells
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: NL71296.000.20; 2019-003620-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No