Treatment of Progressive Multifocal Leukoencephalopathy with Third-Party Allogeneic BK Virus T Cells

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC polyomavirus (JCV) that affects immunosuppressed individuals and has no approved therapy. Here we evaluate the safety and efficacy of third-party, off-the-shelf, partially HLA-matched BK virus-specific T cells (BK-VST) in patients with PML. METHODS: We conducted a single-center phase 2 study where 37 patients received most closely HLA-matched BK-VST at 2.0 x 105 T cells/kg, with additional infusions permitted for subjects who did not achieve a complete response. Twenty-three patients had an underlying diagnosis of hematologic malignancy. Each patient received a median of 2 doses (range, 1-12; IQR 2). Overall response (OR) was defined as virologic clearance with neurologic stabilization or improvement. RESULTS: During 12 months of follow-up, 21 patients (56.8%) achieved an OR, including 16 (43.2%) with a complete response. Responses were rapid (median 23 days) and durable, with no loss of response observed despite limited HLA matching. The 1-year overall survival was 61.1% (95% CI, 41.9-77.4). Patients achieving an OR after the first infusion had markedly improved 1-year survival compared with non-responders (93.3% vs 0%; p<0.001). Higher donor IL-2 and IFN-γ-producing T-cell frequencies and greater HLA matching correlated with clinical benefit. CONCLUSIONS: These data demonstrate that third-party BK-VST infusions are safe and potentially effective, supporting a scalable immunotherapeutic approach for this otherwise fatal disease. (ClinicalTrials.gov NCT02479698).