Phase 1 Study of Immunotherapy Using Autoantigen-Loaded Dendritic Cells in Patients with Anti-Citrullinated Peptide Antigen Positive Rheumatoid Arthritis

Abstract

Background/Purpose

To date, no dendritic cell (DC) immunotherapy has been shown to give a benefit in patients with rheumatoid arthritis (RA). In this prospective phase I study, we evaluated the safety and clinical efficacy of autologous tolerogenic dendritic cell (DC) administration (CreaVax-RA) in patients with RA.

Methods

Twelve RA patients (six for low dose vaccination, 0.5 x 107 cells/injection and remaining six for high dose vaccination, 1.5 x 107 cells/injection) were administrated five times at 2 to 4 week intervals subcutaneously (around inguinal lymph nodes) with each CreaVax-RA, autologous semi-mature DCs pulsed with recombinant PAD4, RA33, citrullinated-filaggrin (cit-FLG) and vimentin antigens. Safety and clinical benefits together with associated immune responses were evaluated as primary and secondary outcomes, respectively, at 14 and 24 weeks after first administration. The major clinical outcomes were assessed by European League Against Rheumatism (EULAR) response.

Results

Among a total of 12 adverse events (AEs) in eight patients, 11 events (91.7%) were restricted in patients treated with low dose (0.5 x 107 cells/inj) while 1 event in patients with high dose (1.5 x 107 cells/inj). All of the AEs were grade 1 or 2 without over grade 3 AE. In ELISPOT assay, the number of IFN-γ-secreting T cells decreased in 91.7% (n = 11/12). The level of antigen-specific autoantibodies significantly decreased in 55.6% (n=5/9) among the autoantibody-positive patients against more than one autoantigen (p < 0.001). The percentage of patients who achieved a good-to-moderate EULAR response ranged over 58.3% (n = 7/12) at 14 weeks after initial administration. The response rate was much higher in high dose group than in low dose group (83.3% vs 33.3%, respectively). The patients without any autoantibodies showed no clinical efficacy

Conclusion

DC administration (CreaVax-RA) was safe and well tolerated in patients with RA in the present phase I study. Preliminary, but clinical outcomes were in good agreement with doses and immune responses. These phase I results warrant further clinical study of high dose CreaVax-RA (1.5 x 107/inj) in patients with RA.