CD19 CAR T Cell Therapy for Treatment-Refractory Seropositive Rheumatoid Arthritis: A Phase 1 Trial

In a phase 1 trail conducted by the Department of Rheumatology and Clinical Immunology at Charité University Medical Center Berlin, with collaborators at Leiden University Medical Center, Erlangen, and the Deutsches Rheuma-Forschungszentrum, six patients with rheumatoid arthritis (RA) that had defied years of drug therapy ceased every immunosuppressant they were taking, received one infusion of CD19-directed chimeric antigen receptor (CAR) T cells, and improved. Published in Nature Medicine, the investigators report that the phase 1 portion of the COMPARE trial met its safety endpoint and cleared the study to advance to randomization against rituximab.

Approved treatments suppress synovitis but leave autoreactive B cells and anti-citrullinated protein antibodies (ACPAs) intact, with cessation of therapy typically resulting in relapse. CD19 is expressed on memory B cells and plasmablasts that CD20-directed rituximab spares, making it a candidate for deeper depletion. This open-label, single-arm study infused mivocabtagene autoleucel (miv-cel), a fully human second-generation CD19 CAR with CD28 costimulation, at 1 × 10⁸ cells following standard fludarabine and cyclophosphamide lymphodepletion, in ACPA-positive patients refractory to at least one conventional and two targeted or biologic disease-modifying antirheumatic drugs. The primary endpoint was cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and adverse events within four weeks.

All six patients (three women, median age 51.5 years, median disease duration 9.6 years) developed CRS, restricted to grades 1 and 2, with onset at a median of 6 days and resolution within 4 days. No ICANS, local immune effector cell-associated toxicity syndrome, serious adverse event, or severe infection occurred; the single dose-limiting toxicity was a grade 3 transaminase elevation that resolved. CAR T cells peaked at a median of 12 days and depleted CD19⁺ B cells in blood, bone marrow, synovium, and lymph nodes, while CD138⁺CD19⁻ plasma cells persisted. DAS28-CRP fell in every patient (median 34% at last follow-up), with remission and an ACR70 response in three. ACPAs against mutated citrullinated vimentin dropped to a median of 94% with seroconversion in four of six, and rheumatoid factor immunoglobulin M in five of six, with vaccine-specific titers holding steady. One patient relapsed at week 44 alongside returning citrulline-reactive plasmablasts.

Reference:

Albach FN, Rehm MC, Hütter-Krönke ML, et al. CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial. Nat Med. 2026. https:doi.org/10.1038/s41591-026-04603-3