BCMA-targeted CAR T-cell therapy in refractory autoimmune diseases: Initial Results from a Phase 1 clinical trial

Abstract

Abstract Introduction: Chimeric antigen receptor (CAR) T-cell therapy offers a promising, targeted approach for treating severe, refractory autoimmune diseases by eliminating autoreactive immune cells. By engineering autologous T cells to recognize disease-specific antigens, this strategy has the potential to induce durable remission beyond conventional immunosuppression. Recent studies using CD19-targeted CAR T cells have shown sustained clinical responses in systemic lupus erythematosus (SLE), idiopathic inflammatory myopathies (IIM), and systemic sclerosis (SSc). B-cell maturation antigen (BCMA), expressed on memory B cells, plasmablasts, and plasma cells, represents an alternative therapeutic target. BCMA-directed CAR T-cell therapy is well established in multiple myeloma (MM), and emerging case reports suggest potential efficacy in autoimmune conditions. We conducted a phase 1, open-label, single-center trial to evaluate the safety and preliminary efficacy of BCMA-targeted CAR T-cell therapy (HBI0101) in patients with severe, treatment-refractory autoimmune diseases. Methods: HBI0101 is an autologous BCMA-targeted CAR T-cell product generated via retroviral transduction of patient-derived T cells. The construct, developed at Hadassah Medical Center, has previously been administered to 143 patients with relapsed/refractory MM and 18 with amyloidosis. In this initial safety phase (October 2024–July 2025), six patients with refractory SLE, SSc, or IIM received lymphodepleting chemotherapy followed by infusion of 450×10⁶ CAR-positive (CAR⁺) T cells. Adverse events (AEs) and clinical responses were closely monitored. Results: Clinical responses were observed across multiple autoimmune phenotypes, with a maximum follow-up of 6 months (mean: 102 days). A patient with IIM demonstrated marked muscle strength improvement, confirmed by neurological examination (manual muscle test for iliopsoas improved from 2/2+ to 5-/4+) and patient report, along with a sustained decline in serum creatine phosphokinase (CPK) levels. Two patients with SSc showed reductions in skin fibrosis, with notable decreases in Modified Rodnan Skin Score (MRSS): from 44 to 20 in case 1, and from 30 to 19.5 in case 2 over the first two months; histological analysis of one patients' skin biopsies revealed early resolution of fibrotic features. A patient with severe SLE and lupus nephritis experienced resolution of edema and systemic symptoms, with normalization of complement levels, serum albumin, hemoglobin, and anti-dsDNA antibody titers. Proteinuria and serum creatinine progressively declined, with creatinine nearing baseline. The patient successfully tapered off corticosteroids and antihypertensive medications. Two additional patients have recently completed treatment and are currently under evaluation. scRNA-seq of urinary cells from a patient with lupus nephritis identified CAR T cells within the urinary compartment. BCMA CAR T-cell therapy was well tolerated, with an acceptable safety profile in this early-phase cohort. Lymphopenia, attributed to lymphodepleting chemotherapy, was observed in all patients. Neutropenia Grade 3-4 occurred in two patients and was managed supportively. The maximal observed cytokine release syndrome (CRS) was Grade 2 in two patients; another two experienced Grade 1 CRS, while two patients showed no CRS. Tocilizumab was administered to 4 patients, with high dose corticosteroids needed in one patient. No neurotoxicity was observed. Conclusions: BCMA-targeted CAR T-cell therapy demonstrated a favorable safety profile in this early-phase trial, with no dose-limiting toxicities or unexpected adverse events. No intervention from the Data Safety Monitoring Board was required. Among four patients with adequate follow-up, all showed signs of significant clinical improvement across diverse autoimmune phenotypes. Specifically, two patients with refractory scleroderma—a particularly difficult-to-treat autoimmune condition, and to the best of our knowledge, not previously targeted with BCMA-directed CAR T therapy—demonstrated marked clinical improvement. These preliminary results support the safety, feasibility, and therapeutic potential of BCMA-targeted CAR T cells as a novel, antigen-specific treatment strategy for refractory autoimmune diseases.