Background/Purpose: 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 (CD38^MidCD24^Mid) and transitional (CD38^HiCD24^Hi) in phenotype at baseline, with a small percentage of memory B cells (CD38^NegCD24^Hi).  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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/correlative-studies-of-caba-201-a-fully-human-autologous-4-1bb-anti-cd19-car-t-cell-therapy-in-patients-with-immune-mediated-necrotizing-myopathy-and-systemic-lupus-erythematosus-from-the-reset-myos/