Background/Purpose:

Rheumatoid arthritis is a chronic autoimmune disease which results from a breakdown of immune tolerance. Current therapies include traditional DMARDs, anti-TNF, B cell depleting therapies and co-stimulation blockade. Despite their efficacious role in reducing disease activity, these therapies non-specifically suppress the immune system, with resulting risks from infection and malignancy. This has led to the development of more specific immune-modulatory therapies in order to specifically switch off the pathological immune response, inducing immune tolerance in an auto-antigen specific manner. Tolerogenic dendritic cells (tolDC) are one such autologous cellular therapy with such potential, with significantly efficacious results in animal models.  We are performing a phase I study of intra-articular tolDC in inflammatory arthritis patients. Our primary and secondary objectives are to assess safety, tolerability and feasibility of treatment; exploratory objectives seek preliminary evidence of a potential therapeutic effect.

Methods:

An ascending dose, randomised, controlled, un-blinded phase I study is currently underway. Three dosing cohorts are planned of 1 million, 3 million and 10 million tolDC administered arthroscopically into an inflamed knee joint following saline washout; controls will receive saline washout only. Each cohort comprises 4 patients (3 active, 1 placebo).  The primary endpoint of the study is the proportion of patients experiencing adverse and serious adverse events following treatment.

Results:

To date 8 subjects with inflammatory arthritis have been treated, 5 with tolDC (3 at 1 million and 2 at 3 million tolDC) and 2 controls.  Manufacture of tolDC failed in a further patient.  TolDC have not induced acute flares of local synovitis (defined as within 5 days of administration). Two delayed knee flares occurred between 11 and 14 days from treatment (one in a subject receiving 1 million tolDC and 1 receiving 3 million tolDC).  Two patients experienced a systemic flare of their arthritis 14 days after treatment (1 in subject receiving one million tolDC and 1 in a subject receiving 3 million tolDC).  There have been no knee or systemic arthritis flares in control patients. To date patient acceptability has been high but there has been no evidence of a beneficial effect of tolDC administration. There have been two infections: one wound infection at an arthroscopy port and one pneumonia.  

Conclusion:

In this ascending dose phase I study of intra-articular tolDC we have not seen evidence of acute toxicity.  To date we have also not witnessed a beneficial effect and local inflammation has recurred following intervention.  Two systemic flares were judged unrelated to therapy. Our results to date suggest that intra-articular tolDC do not induce an acute flare of inflammatory arthritis and is acceptable to patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autologous-tolerogenic-dendritic-cells-in-rheumatoid-and-inflammatory-arthritis/