Poster Session A
Myopathic rheumatic diseases (polymyositis, dermatomyositis, inclusion body myositis)
Daniel Nunez, PhD (he/him/his)
Cabaletta Bio
Philadelphia, Pennsylvania, United States
No financial relationships with ineligible companies to disclose
CD19 targeting chimeric antigen receptor (CAR) T cells have demonstrated durable drug-free responses and remission in patients with idiopathic inflammatory myopathies (IIM) and systemic lupus erythematosus (SLE) in an academic study series. As a fully human, autologous 4-1BB anti-CD19-CAR T cell therapy, CABA-201 is being evaluated in multiple B cell-mediated autoimmune diseases. RESET-Myositis (NCT06154252) and RESET-SLE (NCT06121297) are ongoing phase I/II clinical trials evaluating the safety & efficacy of CABA-201 in four independent myositis cohorts of immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), dermatomyositis and juvenile IIM and two separate SLE cohorts of non-renal SLE and lupus nephritis (LN). We report on the initial correlative data of the first 12 weeks & 28 days post- CABA-201 treatment in the first IMNM and the first SLE patient, respectively.
Methods:
Sera and PBMCs were collected from SLE & IIM subjects before & after CABA-201 infusion. Sera were evaluated for cytokines by electro-chemiluminescence immunoassay. Sera were also evaluated for IIM, SLE, & pathogen associated antibodies via immunoassay. Flow cytometric analyses were performed on CART and B cells. CART cells were quantified post-infusion via dPCR. Cytolytic analyses of the CABA-201 infusion product were performed via IncuCyte assay.
Results: Both patients tolerated CABA-201 treatment with no Serious Adverse Events (SAE), Cytokine Release Syndrome (CRS), or Immune effector cell-associated neurotoxicity syndrome. The CABA-201 infusion product from both patients consisted of predominantly CD4+ effector memory CAR T cells and exhibited in vitro cytolytic activity towards a NALM6 target cell line. Post-infusion, CABA-201 expansion peaked at day 15 in both patients, which was preceded by a serum IFN-γ peak on day 5 and day 8 for the SLE and the IMNM patient, respectively. Leukocyte and lymphocyte counts dropped quickly and transiently after a standard preconditioning regimen of fludarabine (25mg/m2/dy x 3) and cyclophosphamide (1000mg/m2) which inversely corresponded with a transient peak in serum IL-15 levels in both patients. Peripheral B cells in the IMNM patient were predominantly naïve (CD38MidCD24Mid) and transitional (CD38HiCD24Hi) in phenotype at baseline, with a small percentage of memory B cells (CD38NegCD24Hi). B cells in both patients were reduced rapidly following infusion, and full B cell depletion was achieved at day 15 post-infusion for both patients (Figure). Serum levels of B cell activating factor (BAFF) increased throughout the first month in response to B cell depletion. In the IMNM patient, peripheral B cells repopulated by week 8 and were a majority (over 90%) transitional in phenotype with no memory B cells detected. Antibodies associated with infectious diseases and standard vaccinations remained stable in both patients whereas serum levels of myositis-specific and associated autoantibodies decreased in the IMNM patient over the first three months.
Conclusion:
These emerging data detail the pharmacokinetics and pharmacodynamics of CABA-201 in IIM and SLE. Evaluation of the selected CABA-201 dose continues in the ongoing RESET-Myositis and RESET-SLE trials.
Figure Legend: CD19+CD20+ B cells post-CABA-201 infusion. CD19+CD20+ B cells as determined by flow cytometry from the SLE subject (red line) and IMNM subject (blue line) over the first 29 days post-infusion.
D. Nunez: CabalettaBio, 3, 11; J. Volkov: Cabaletta Bio, 3; J. Stadanlick: Cabaletta Bio, 3, 11; Z. Vorndran: CabalettaBio, 3, 11; A. Ellis: CabalettaBio, 3, 11; M. Werner: Cabaletta Bio, 3, 11; J. Cicarelli: Cabaletta Bio, 3, 11; J. Williams: Cabaletta Bio, 3, 11; F. Nezhad: Cabaletta Bio, 3; T. Furmanak: Allogene Therapeutics, 3, Cabaletta Bio, 3; Q. Lam: Cabaletta Bio, 3; R. Estremera: Cabaletta Bio, 3, Exact Sciences, 3; Y. White: Cabaletta Bio, 3; J. Hogan: Cabaletta Bio, 3; C. Miller: Cabaletta Bio, 3; T. Mozaffar: AstraZeneca, 2, Merck/MSD, 1, UCB, 1, 2; S. Sheikh: AstraZeneca, 2, Biogen, 2, Cabaletta Bio, 2, GlaxoSmithKlein(GSK), 2; D. Chang: Cabaletta Bio, 3; S. Basu: CabalettaBio, 3, 11.