To evaluate the safety, tolerability, and immunologic effects of NT-I7, a long-acting recombinant interleukin-7 (rhIL-7-hyFc), as an immune-reconstitution strategy for lymphopenia in patients with progressive multifocal leukoencephalopathy (PML).

PML is a life-threatening, opportunistic infection caused by the JC-virus. Survival depends on successful immune reconstitution. Since IL-7 is critical for T-cell development and survival, recombinant formulations have been used anecdotally in PML, with survival associated with lymphocyte expansion. NT-I7, a long-acting formulation, may provide sustained lymphocyte recovery, but effects in PML have not been evaluated.

This single-site, open-label, pilot study enrolled adults with definite or probable PML and CD4 and/or CD8 lymphopenia <200 cells/µL. Participants received intramuscular NT-I7 and underwent clinical assessment, lymphocyte-phenotyping, JC-viral load quantification, MRI, and exploratory analyses including intracellular cytokine-staining and T-cell receptor excision-circle (TREC) measurements.

Twelve patients with diverse underlying diseases were enrolled (hematologic-malignancy: n=6). Patients had severe disability (median mRS-4; Interquartile range (IQR): 4–4), marked CD4+ lymphopenia (median 94 cells/µL; IQR: 50–115), and high JCV viral-load (median CSF-JCV-DNA 4.8 log copies/mL; IQR:3.7–5.9). Nine (75%) achieved >50% increase in lymphocyte count, similar across CD4/CD8 subsets. Mild adverse events included fatigue, rash, and injection-site reactions; one serious adverse-event was probably related to study drug (thrombotic microangiopathy). Effect on JC-viral load was variable, and 25% developed new enhancement per MRI, suggestive of immune-reconstitution. Despite robust lymphocyte expansion, only 2 patients survived PML. Survivors demonstrated increased anti-JCV T-cell responses following treatment while TREC analysis showed no thymic activity, suggesting lymphocyte expansion resulted primarily from homeostatic proliferation.

NT-I7 was well-tolerated and expanded lymphocytes in most PML patients. The modest impact on PML survival underscores challenges related to advanced disease, pre-treatment immune repertoire and toxicities influenced by underlying disease. This study provides key insights into IL-7–driven immune reconstitution that will guide future optimization of IL-7–based therapeutic strategies.