Exploratory Study of Anti-BCMA-CD19 CAR-T Cell Therapy in Relapsed or Refractory IgG4-Related Disease

This is a Phase 2?Phase 2 A study that tests whether a treatment has the intended effect and continues to check safety, usually in a larger group than phase 1., open-label?open-label No masking is used, so the assigned intervention is not deliberately hidden from participants or study staff., single-arm?single-arm All participants receive the same treatment or follow the same plan. There is no comparison group within the study. exploratory clinical trial using a 3+3?3+3 Groups of participants receive increasing doses of a treatment, one group after another, to find a dose that can be given safely. dose-escalation design to assess the safety, feasibility, and preliminary efficacy of autologous anti-BCMA-CD19 chimeric antigen receptor T (CAR-T) cell therapy in patients with relapsed or refractory IgG4-related disease (IgG4-RD). Background IgG4-RD is a chronic, immune-mediated fibroinflammatory disorder that can involve multiple organs, including the pancreas, bile ducts, salivary glands, kidneys, lungs, and retroperitoneum. Although standard treatments such as glucocorticoids and anti-CD20 monoclonal antibodies (e.g., rituximab) are effective for most patients, some develop treatment resistance, frequent relapses, or contraindications?contraindications A reason a particular test or treatment should not be used for a person, for example a metal implant that rules out an MRI scan. to conventional immunosuppressive?immunosuppressive A medicine that reduces the activity of the immune system. Studies of autoimmune conditions often require a stable dose, a prior failure, or a washout of such medicines. agents. This creates an unmet clinical need for novel therapeutic strategies. Recent translational studies show that IgG4-RD lesions often contain abundant CD19+ B cells, plasmablasts, and long-lived plasma cells expressing B-cell maturation antigen (BCMA), many of which may be resistant to conventional B-cell depletion. Dual-target CAR-T cells directed against both CD19 and BCMA may achieve more complete depletion of pathogenic B-lineage cells and offer a promising treatment for refractory IgG4-RD. Methods Eligible participants will undergo leukapheresis for autologous peripheral blood mononuclear cell (PBMC) collection. Cells will be transduced ex vivo with a lentiviral vector encoding a CAR construct targeting CD19 and BCMA, then expanded and prepared for infusion. Lymphodepletion chemotherapy with cyclophosphamide (250 mg/m\^2/day, IV) and fludarabine (30 mg/m\^2/day, IV) will be given on Days -5 to -3. The doses of fludarabine and cyclophosphamide may be adjusted based on the patient's condition. CAR-T cells will be infused on Day 0 at one of three sequential dose levels (1×10\^6, 2×10\^6, or 3×10\^6 CAR+ T cells/kg, ±20%). Participants will be followed regularly for safety (adverse events?adverse events Any unwanted medical problem that happens during a study, whether or not it was caused by the treatment. A 'serious' adverse event is one that meets specific criteria, such as causing death, being life-threatening, requiring or prolonging hospital admission, causing significant disability, or another medically important outcome. [AEs], serious adverse events [SAEs], cytokine release syndrome?cytokine release syndrome A reaction in which the immune system releases a large amount of signalling proteins at once, causing fever and sometimes low blood pressure or breathing problems. It can occur after some immune therapies, such as CAR-T cells or bispecific antibodies. [CRS], immune effector cell-associated neurotoxicity syndrome?immune effector cell-associated neurotoxicity syndrome Nervous-system side effects, such as confusion or difficulty speaking, that can occur after some immune therapies. Usually temporary, but monitored closely. [ICANS]), pharmacokinetics?pharmacokinetics How the body absorbs, distributes, breaks down and removes a drug. It is studied by measuring drug levels or related substances at set times after a dose. (CAR-T cell expansion and persistence), and immunologic responses. Endpoints?Endpoints Something the study measures to judge its results, such as a symptom score, a blood test or survival. Outcomes are grouped as primary, secondary and sometimes exploratory. The primary endpoints are safety (incidence of dose-limiting toxicities?dose-limiting toxicities A side effect, defined in advance, that is severe enough to limit how far the dose can be raised in a dose-escalation study. How many such events stop escalation is set by the study's rules. [DLTs] within 28 days post-infusion) and efficacy (change in IgG4-RD Responder Index [RI] at Week 12 and Week 26). Secondary endpoints include changes in target lesion size, serum IgG4, IgE, and eosinophil counts, as well as histopathologic changes in affected tissue. Exploratory Analyses Exploratory studies will assess immune cell profiles in blood, bone marrow, and tissue biopsies using flow cytometry, multiplex cytokine assays, and spatial or single-cell transcriptomic techniques.