BCMA-targeted CAR T cells for multi-refractory primary immune thrombocytopenia: A pilot study Free

Background:Primary immune thrombocytopenia (ITP) is a bleeding disorder primarily driven by pathogenic anti-platelet autoantibodies produced by autoreactive B cells and plasma cells. Recent studies have demonstrated that CAR-T cell therapy effectively depletes B cells within tissues and secondary lymphoid organs, thereby preventing autoantibody-mediated disease relapse. Here, we report the results from a single-center, single-arm, open-label pilot study (NCT06519565) evaluating autologous BCMA CAR T cells (PRG-1801) in patients with primary multi-refractory ITP.

.Methods: Eligible patients were aged 18 to 75 years, had a ≥6-month history of primary ITP, tested positive for platelet-specific autoantibodies, and had failed multiple prior first- and second-line therapies, with platelet counts persistently below 30×10⁹/L. After enrollment, leukapheresis collected PBMCs. Two days later, patients underwent a 3-day lymphodepleting chemotherapy regimen with fludarabine (25 mg/m²) and cyclophosphamide (250 mg/m²) on Days -5 to -3. Fresh PRG-1801 CAR-T cells were infused on D0. The CAR construct included a BCMA single-domain antibody, CD8 hinge, transmembrane domain, 4-1BB co-stimulatory, and CD3ζ signaling domains, delivered via lentiviral transduction. Two dose levels (DLs) of PRG-1801 were tested: total doses of 35×10⁶ and 100×10⁶ CAR-T cells. Following infusion, patients underwent one-month in-hospital safety monitoring and will be followed for 24 months. No platelet-elevating agents (e.g., IVIG, corticosteroids, platelet transfusions, or TPO receptor agonists) were administered following CAR-T infusion, except when clinically indicated for the management of adverse events, such as cytokine release syndrome (CRS).Peripheral blood samples were collected on Days 0, 2, 4, 6, 8, 10, 12, 14, 21, and 28, as well as at Months 2, 3, 6, 9, 12, 18, and 24 for evaluations of pharmacokinetics (PK), pharmacodynamics (PD), immunologic effects, and safety following PRG-1801 infusion.

Results: Between August 2024 and July 2025, four patients (3 females, 1 male; median age 52 [33–70]) were enrolled. All had failed ≥4 prior first- and second-line therapies and had platelet counts persistently <30×10⁹/L. The first patient received 35×10⁶ CAR-T cells, and three 100×10⁶. Follow-up for the first patient was 330 days; the higher-dose patients were followed for 150, 49, and 28 days. Common AEs included cytopenia (100%), CRS (75%), and infections (50%). Neither grade ≥3 immune effector cell–associated hematotoxicity (ICAHT) nor immune effector cell-associated neurotoxicity syndrome (ICANS) occurred. All high-dose patients achieved complete response (CR; platelet ≥100×10⁹/L) within 28 days post-infusion and maintained a drug-free state. The low-dose patient achieved response (R; platelet ≥30×10⁹/L and ≥2-fold increase from baseline without active bleeding) at Month 6, but with delayed and less stable efficacy.

Immunophenotyping revealed shifts toward a naïve B-cell phenotype in all patients: class-switched memory B cells decreased, non-switched memory B cells increased, and plasma cells were nearly eliminated. However, only in the low-dose patient, plasma cells rebounded during immune reconstitution, suggesting incomplete clearance. T-cell subset analysis revealed similar overall CD4⁺ and CD8⁺ T cell proportions, but notable differences in specific subsets. The low-dose patient had persistently high levels of terminally differentiated effector CD8⁺ T cells (TEMRA) pre- and post-treatment, associated with refractory ITP; these declined in high-dose patients. Terminally differentiated CD4⁺ T cells increased post-treatment in the low-dose group but decreased in the high-dose group. Trends in effector memory, naïve, and central memory T cells were consistent across patients.

Conclusions: These results provide preliminary evidence that CAR-T cell therapy is effective in refractory ITP patients driven primarily by B-cell–mediated mechanisms, enabling rapid and sustained clearance of anti-platelet autoantibodies, prompt platelet recovery, and drug-free remission. Given the heterogeneity of ITP, patients with T cell driven disease may be less susceptible to CAR T directed at the B cell lineage.