Autologous IA Tolerogenic Dendritic Cell Therapy for Inflammatory Arthritis

Intra-articular (IA) autologous tolerogenic dendritic cell (tolDC) therapy was a safe, feasible, and acceptable treatment option for patients with inflammatory arthritis of the knee, according to data from a randomized, dose escalation phase I trial published in the Annals of the Rheumatic Diseases.

Dendritic cells participate in the immune response against pathogens, tumors, and play an important role in maintaining self-tolerance. Breakdown of self-tolerance and production of autoantibodies is implicated in the pathogenesis of several inflammatory disease states. Researchers designed a study to assess the safety, feasibility, and acceptability of tolDC therapy in patients with inflammatory arthritis and to determine potential effects on local and systemic disease activities (ClinicalTrials.gov Identifier NCT01352858, Autologous Tolerogenic Dendritic Cells for Rheumatoid Arthritis [AutoDECRA]).

Eligible study participants had active inflammatory arthritis of the knee joint (with effusion) who had failed at least one disease-modifying antirheumatic drug (DMARD) in the past.  TolDC treatment was added to the patient’s baseline DMARD and anti-inflammatory therapy. Intramuscular glucocorticoids and intraarticular knee joint injections were not permitted for 6 weeks prior to the study.

Synovial fluid (SF) was aspirated from an inflamed knee joint under high resolution ultrasound and was treated with heparin and hyaluronidase. Routine leukapherisis was used to harvest white blood cells. Peripheral blood mononuclear cells were isolated by density gradient centrifugation and CD-14 positive selection. Cells were cultured for 7 days with the addition of cytokines and immunosuppressive drugs, and dendritic differentiation was induced. In the process cells were also exposed to autoantigens in autologous SF.

The study included 3 dosing cohorts of 1×10⁶, 3×10⁶, and 10×10⁶ viable tolDC, which was administered with a single arthroscopic injection following saline irrigation of an inflamed knee. Each cohort included 3 participants with the primary outcome being defined as disease flare in the inflamed disease within 5 days of arthroscopy.  Control participants received only saline irrigation.

Researchers assessed feasibility by successful tolDC manufacture, and they assessed acceptability with patient questionnaires. The effects on disease activity were evaluated with an arthoscopic synovitis score, a disease activity score (DAS28), and the Health Assessment Questionnaire (HAQ).

There were no observed knee flares within 5 days of treatment. Arthoscopic synovitis was present in all participants by day 14, with the exception of 1 patient who received 10×10⁶ tolDC and another patient who declined at day 14 arthoscopy due to remitting symptoms. Both patients remained stable throughout 91 days of observation. Local glucocorticoid was administered for arthroscopic synovitis in all patients in the 1×10⁶ and 3×10⁶ tolDC cohorts, as well as all three controls. 

There were no observed trends in DAS28 or HAQ score and there were no consistent immunodulatory effects in peripheral blood. The researchers also noted that 9 out of 10 manufactured products met quality control release criteria, and acceptability of the protocol by participants was high.

“These data emphasize the safety and potential utility of tolDC across a range of arthritides with differing etiology,” the authors concluded. “Notably, targeting IL-17 is effective in psoriatic arthritis and tolDC deviate T-cells in [collagen-induced arthritis] from IL-17 to IL-10 production.”

Summary and Clinical Applicability

The authors of the study concluded that tolDC therapy is safe for patients with inflammatory arthritis with an inflamed knee. “There are advantages and disadvantages to our current protocol. Nonetheless, we believe that [the Autologous Tolerogenic Dendritic Cells for Rheumatoid and Arthritis trial] has defined a safe, and potentially active, dose of tolDC on which to base future work,” they stated.

They also suggest that future studies address the efficacy of the IA route in tolDC therapy. The IA route provides a positive safety read-out, but it may provide a more challenging environment for tolDC to demonstrate efficacy. Researchers should consider whether the IA route could provide a systemic effect for these patients.

Limitations and Disclosures

This study was not blinded. In addition, 12 adverse effects were identified as being related to intervention, including 2 wound infections, 1 SF leak, an episode of citrate toxicity related to leukapheresis, as well as a vasovagal episode related to arthroscopy. These complications highlight the relatively invasive nature of delivering tolDCs via IA arthroscopic intervention.

Although no RA disease flare occurred within the defined timeframe of 5 days, 4 episodes of target knee or systemic synovitis were noted between days 7 and 10 in study participants receiving 1×10⁶ or 3×10⁶ tolDC.

Additionally, 2 of 3 study participants who received 10×10⁶ tolDC did not require local glucocorticoid throughout the study as compared to those participants in the 1×10⁶ and 3×10⁶ tolDC cohorts who received local glucocorticoids for arthroscopic synovitis on day 14.

“We cannot state unequivocally that tolDC therapy is safe but it is possible that most participants in this small trial received a subtherapeutic dose of tolDC, the ‘flares’ and arthroscopic synovitis on day 14 reflecting the natural history of synovitis following joint irrigation,” the authors noted.

Reference

Bell GM, Anderson AE, Diboll J, et al. Autologoustolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2016; doi: 10.1136/annrheumdis-2015-208456.