Session Type: Abstract Submissions (ACR)
Rheumatoid arthritis (RA) is a chronic autoimmune disease which results from a breakdown of immune tolerance. Despite their efficacy current RA therapeutics, including biologic and non-biologic DMARDs, generally require chronic administration with the associated risk of adverse effects. The concept of therapeutic tolerance states that it should be possible to reprogram unwanted immune responses, including autoimmunity, and reset the immune system to self-tolerance. Although the concept has been achieved in animal models of autoimmunity and transplantation it has not yet been convincingly demonstrated in humans. We have developed a potentially tolerogenic therapy, autologous tolerogenic dendritic cells (tolDC), and now report the results of a phase 1 safety trial in patients with inflammatory arthritis. The secondary objectives were to assess tolerability and feasibility; exploratory objectives include preliminary evidence of potential efficacy including biomarkers.
This was an ascending dose, randomised, controlled, un-blinded phase I study. Participants had a chronic inflammatory arthritis (75% RA) with an actively inflamed knee joint. Background therapy was maintained throughout the trial. There were three dosing cohorts of 1 million, 3 million and 10 million tolDC; controls received saline washout only. Following screening, participants underwent leukapheresis and leukocytes were transferred to a GMP facility. CD14+ monocytes were positively selected and tolDC differentiated according to our published methods1. During differentiation tolDC were loaded with autologous synovial fluid as autoantigen. After 7 days tolDC were administered arthroscopically into the inflamed knee joint following saline washout. Synovial biopsies were taken arthroscopically at baseline and again 14 days later, when intra-articular glucocorticoid was administered for persistent inflammation. The primary endpoint of the study was the proportion of patients experiencing a flare of target knee joint inflammation within 5 days of tolDC administration (knee flare). Secondary endpoints were patient acceptability and the success rate of tolDC preparation.
TolDC were successfully manufactured from 9 patients. The product marginally failed quality control in a tenth case. No knee flares were observed in patients or controls. In most participants there was residual inflammation at day 14 arthroscopy except for two patients in the 10 million tolDC cohort. There was one SAE (flare of RA on day 70, requiring hospital admission and subsequent pneumonia) and several AEs, most of which were deemed unrelated to therapy. Patient acceptability of the intervention was high.
We have peformed a phase 1 study of intra-articular tolDC in patients with inflammatory arthritis. The intervention appeared safe, feasible and acceptable to participants. We are currently planning tracking studies, to study the fate of administered cells, and biomarker analysis.
1Harry RA, Anderson AE, Isaacs JD, Hilkens CM. Generation and characterisation of therapeutic tolerogenic dendritic cells for rheumatoid arthritis. Ann Rheum Dis 2010;69:2042-2050.
A. E. Anderson,
J. D. Isaacs,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autologous-tolerogenic-dendritic-cells-for-rheumatoid-and-inflammatory-arthritis/