Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease driven by dysregulated B-cell responses, including autoreactive B cells producing antibodies against citrullinated proteins (ACPA). CD19-directed chimeric antigen receptor (CAR) T-cell therapy represents a novel therapeutic approach capable of inducing deeper and more durable B-cell depletion than existing therapies, thereby potentially enabling immune reset and sustained remission [1-5]. The COMPARE trial (EU CT: 2024-514955-13-00) is the first study evaluating CD19 CAR T-cell therapy in ACPA-positive RA patients treated with mivocabtagene autoleucel (miv-cel, KYV-101).

Objectives: To establish a robust multimodal pipeline to comprehensively phenotype total and autoreactive B-cell populations and to assess B-cell depletion and reconstitution following CAR T-cell therapy.

Methods: In the prospective, open-label Phase I/II COMPARE trial, adults with active, ACPA-positive, treatment-refractory RA were enrolled. In Phase I, six participants received a single infusion of miv-cel, an autologous, fully human CD19-directed CAR T-cell therapy with CD28 costimulation. Serological markers, including ACPA and rheumatoid factor (RF) titers, and B-cell kinetics from trial participants were longitudinally assessed for 16 to 36 weeks. Biospecimens were obtained from synovial tissue, bone marrow, lymph nodes, and peripheral blood. Cells were analyzed using high-parameter flow cytometry, including Cyclic Citrullinated Peptide 4 (CCP4) tetramer staining to identify and phenotype rare ACPA-positive B cells. Molecular profiling incorporated single-cell sequencing and B-cell receptor (BCR) repertoire analysis [6].

Results: Miv-cel treatment resulted in complete peripheral B-cell depletion and marked reductions in circulating ACPA and RF IgM titers. Although two patients demonstrated peripheral B-cell reconstitution to >0.1/nL, ACPA titers continued to decline. Consistent with these results, clinical status improved in all patients. To date, no re-emergence of peripheral autoreactive memory B cells has been observed. Instead, reconstituted total B cells displayed a predominantly naive phenotype, suggesting repopulation from early progenitors rather than the persistence of antigen-experienced clones. Deep phenotyping is ongoing to assess the depth of total and ACPA-expressing B-cell depletion within synovial and bone marrow compartments.

Conclusions: CD19 CAR T-cell therapy with miv-cel induces profound depletion of total B cells and reshapes early B-cell reconstitution toward a naive phenotype in ACPA-positive RA, supporting the concept of immune reset.

REFERENCES: [1] Haghikia A, et al. Ann Rheum Dis. 2024.

[2] Albach FN, et al. Rheumatology (Oxford). 2025.

[3] Lidar M, et al. Ann Rheum Dis. 2025.

[4] Li Y, et al. Cell res. 2025.

[5] Albach FN, et al. EULAR Rheumatology Open. 2025.

[6] Kerkman, P. F et al. Ann Rheum Dis. 2016.

Acknowledgments: NIL.

Disclosure of Interests: Thanh Hang Le Kyverna Therapeutics, Marie Rehm: None declared, Arne Sattler: None declared, Artur Wilhelm: None declared, Anja Fleischmann: None declared, Stefano Bianco: None declared, Fredrik N. Albach: None declared, Edgar Wiebe: None declared, Vincent Casteleyn: None declared, Murat Torgutalp: None declared, Arnd Kleyer AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Lilly, Novartis, UCB, AbbVie, Amgen, Alfasigma, Bristol-Myers Squibb, Janssen-Cilag, Lilly, Novartis, UCB, AbbVie, Bristol-Myers Squibb, Lilly, Novartis, UCB, AbbVie, Janssen-Cilag, Jan Zernicke: None declared, Dominic Borie Kyverna Therapeutics, Marie Luise Hütter-Krönke: None declared, Ulrich Keller: None declared, Olaf Penack: None declared, Lars Bullinger: None declared, Antonia Busse: None declared, Julia Giezen: None declared, Rene Toes: None declared, Hans Ulrich Scherer: None declared, David Simon AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Lilly, Novartis, UCB, AbbVie, Amgen, Alfasigma, Bristol-Myers Squibb, Janssen-Cilag, Lilly, Novartis, UCB, AbbVie, Bristol-Myers Squibb, Lilly, Novartis, UCB, AbbVie, Janssen-Cilag, Gerhard Krönke Kyverna Therapeutics, Kyverna Therapeutics.