American College of Rheumatology

Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

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Feasibility, Safety and Clinical Effects of a Single Intradermal Administration of Autologous Tolerising Dendritic Cells Exposed to Citrullinated Peptides in Patients with Rheumatoid Arthritis.

Thomas,  Ranjeny, Street,  Shayna, Ramnoruth,  Nishta, Pahau,  Helen, Law,  Soi, Brunck,  Marion, Hyde,  Claire

Background/Purpose:

Bone marrow-derived dendritic cells modified with the irreversible NF-kappaB inhibitor, Bay11–7082 (Bay-DCs), exposed to arthritogenic antigen, transfer antigen-specific suppression of inflammatory arthritis in mice, through induction of regulatory T cells. We carried out a phase I clinical trial of autologous peripheral blood (PB) Bay-DCs exposed to citrullinated peptide antigens (known as Rheumavax) in HLA-DR shared epitope (SE)+ anti-citrullinated peptide antibody (ACPA)+ rheumatoid arthritis (RA) patients. The aims of this phase I first-in-man study were to demonstrate feasibility and safety of autologous peripheral blood (PB) DC immunotherapy, and to describe its clinical and immune effects.

Methods:

Bay-DCs were generated from 250ml PB under good laboratory practice (GLP) conditions after purification of PB mononuclear cells by density sedimentation, and PB monocytes by elutriation, then culture in the presence of RPMI, 10% human serum, 400U/ml GM-CSF and 800U/ml IL-4 and 2.5 uM Bay11–7082 for 60h. During the final 18h, cells were pulsed with a mixture of four citrullinated peptide antigens (cit-vimentin 447–455, cit-fibrinogen beta chain 433–441, cit-fibrinogen alpha chain 717–725, cit-collagen type II 1237–1249). Rheumavax was administered intradermally once to each group of 9 RA patients on usual disease modifying drugs (DMARDs) in 2 progressive vaccine dose levels (total of 18 vaccinated subjects) in an escalating dose regimen. Group 1 received 1 million DCs and group 2 received 5 million DCs on day 1 of study. Open label control group of 11 patients received usual DMARDs. The primary outcomes were 1. clinical, and 2. laboratory measures of safety and 3. citrullinated peptide-specific tolerance; the secondary outcome was clinical response. Patients were evaluated at baseline, monthly for 3 months and finally at 6 months.

Results:

We recruited 29 SE+ ACPA+ patients with RA, including 18 females, with mean age 56 (range 38–76), mean disease duration of 5.4 (range 1–10) years, and treated with at least 1 DMARD, to the study. All Bay-DC cultures were sterile. Rheumavax was well-tolerated at both doses and did not provoke local skin reactions, lymphadenopathy, allergic reactions, infections or immediate disease flares. Adverse events were all grade 1 (of 4) severity and included headache (2), and laboratory evidence of anemia (3), lymphopenia (3), leukopenia (3) and elevated alkaline phosphatase (2) or AST (1). DAS scores decreased below 2.5, sometimes for prolonged periods, in 7/9 Rheumavax recipients who commenced the trial with DAS4vCRP>2.5. DAS scores were stable in 7/9 Rheumavax patients who commenced the trial with DAS4vCRP<2.5. Systemic effects of Rheumavax were demonstrated by reductions in CRP, ESR and the homeostatic model of insulin resistance (HOMA-IR). Immune tolerance outcomes will be discussed.

Conclusion:

These data demonstrate the feasibility and safety of a single intradermal administration of autologous tolerising dendritic cells exposed to citrullinated peptides in RA patients.

To cite this abstract, please use the following information:
Thomas, Ranjeny, Street, Shayna, Ramnoruth, Nishta, Pahau, Helen, Law, Soi, Brunck, Marion, et al; Feasibility, Safety and Clinical Effects of a Single Intradermal Administration of Autologous Tolerising Dendritic Cells Exposed to Citrullinated Peptides in Patients with Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2430
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