NT-I7 in progressive multifocal leukoencephalopathy: Immune reconstitution and antiviral immunity in a pilot study

Presented at AAN 2026: Long-Acting IL-7 (NT-I7) as an Immune Reconstitution Strategy in PML: Immunological and Clinical Outcomes from a Pilot Study. LS1: Late-breaking Science 1. April 18-22, Chicago, USA.

Could you briefly outline the current unmet needs in PML, and why effective immune reconstitution remains central to improving outcomes in this setting?

PML remains a disease with significant unmet clinical needs. It is a rare and heterogeneous condition, occurring across diverse underlying diseases and degrees of immune dysfunction, which complicates both diagnosis and therapeutic development. Delays in diagnosis are common, as early imaging findings may be misinterpreted.

Most importantly, there are currently no validated treatments. Management is therefore centered on restoring immune function when possible, for example through antiretroviral therapy in HIV or withdrawal of immunosuppression. However, these approaches are not feasible in many patients and, even when implemented, often fail to act quickly enough to prevent the rapid progression of PML, which remains fatal in a substantial proportion of cases.

As a result, research efforts have increasingly focused on experimental strategies to support immune reconstitution, some of which have shown promising signals. This emphasis reflects the central role of immune failure in PML pathogenesis. The disease arises from impaired immune surveillance, allowing JC virus reactivation and uncontrolled viral replication within the central nervous system.

Clinical recovery depends on the restoration of effective antiviral T-cell responses capable of controlling this process. However, immune reconstitution is not uniform, and its success depends on both the timing and quality of the immune response. Developing strategies that not only restore immune cell numbers but also promote functional antiviral immunity remains a key challenge in the field.

What was the rationale for evaluating NT-I7 in PML, and how might IL-7-mediated lymphocyte expansion help address the profound lymphopenia often seen in these patients?

The rationale for evaluating NT-I7 in PML stems directly from the central role of lymphopenia, particularly CD4 lymphopenia, in disease pathogenesis. Severe depletion of T cells is a major risk factor for both the development and progression of PML, and therapeutic strategies have therefore focused on restoring immune competence.

Interleukin-7 is a key cytokine involved in T-cell survival, homeostasis and proliferation, making it an attractive candidate for immune reconstitution. NT-I7 is a long-acting formulation designed to induce sustained lymphocyte expansion. Prior retrospective data suggested that achieving greater than a 50% increase in lymphocyte counts may be associated with improved survival in PML, providing a biologic rationale for prospective evaluation.

By expanding both naïve and memory T-cell populations, IL-7 has the potential to augment antiviral immunity in lymphopenic patients. However, an important question is whether this expansion translates into functional JC virus-specific immune responses. Our study was therefore designed not only to assess the safety of the product and the magnitude of lymphocyte recovery, but also to better understand the quality of the immune response induced by IL-7.

Could you talk us through the design of this pilot study and the key immunologic and clinical findings, particularly in terms of lymphocyte recovery, JC viral load and safety?

We conducted a single-site, open-label pilot study evaluating NT-I7 in patients with PML and severe lymphopenia, allowing for redosing and dose escalation. Participants underwent longitudinal, systematic clinical, virologic and immunologic assessment, including JC viral load quantification and MRI.

NT-I7 was generally well tolerated, with predominantly mild adverse events and one serious event considered possibly related. Most patients demonstrated robust lymphocyte expansion, with the majority achieving greater than a 50% increase across CD4 and CD8 subsets.

However, JC viral load responses were variable, and clinical outcomes remained limited, with only two patients surviving. Notably, only the survivors demonstrated increased JC virus-specific T-cell responses following treatment, highlighting a distinction between quantitative lymphocyte expansion and functional antiviral immunity.

Although most patients experienced robust lymphocyte expansion, survival remained limited. What do these findings tell us about the challenges of treating advanced PML and the factors that may influence response to immune-restorative strategies?

These findings must be interpreted in the context of advanced disease. Compared with our natural history cohort and prior IL-7 experience, including the series reported by Lajaunie et al., this cohort presented with more severe PML, reflected by higher JC viral load in CSF and greater disability.

In addition, although most patients experienced robust lymphocyte expansion, this did not consistently translate into clinical benefit, suggesting that quantitative immune restoration alone is insufficient.

Our data indicate that the quality of the immune response is critical. Only the two survivors demonstrated increased JC virus-specific T-cell responses, while other markers of immune activation, such as declines in JC viral load or gadolinium enhancement, were variable and did not reliably correlate with outcome.

These findings suggest that response depends on both the expansion of functional antiviral immunity and the stage of disease at treatment initiation.

Based on these results, what are the next steps for NT-I7 or other IL-7-based approaches, and how might future studies optimize patient selection or timing of treatment in PML?

These results highlight several important directions for future studies. A key priority is understanding why only a subset of patients demonstrate expansion of JC virus-specific T-cell responses, as this appears to be more closely associated with clinical outcome than lymphocyte expansion alone. Defining the mechanisms underlying this selective expansion will be critical and may ultimately guide patient selection.

Ongoing analyses, including single-cell sequencing, are focused on defining the immune cell subsets and activation states responsible for this effect and may inform future therapeutic strategies.

In addition, earlier intervention may improve outcomes before irreversible CNS injury has occurred. Our cohort consisted of patients with advanced disease, which likely limited the impact of immune restoration.

What do you think were the most important therapeutic and treatment updates presented at American Academy of Neurology 2026?

AAN 2026 highlighted continued momentum in immune-based therapies across neurologic disease, with a particular emphasis on understanding not just whether treatments work, but how they work.

In neuroinfectious disease and PML specifically, studies reinforced that restoring immune function is necessary but not sufficient. What matters is the quality and specificity of the immune response.

More broadly, these developments reflect a shift toward mechanism-driven and personalized strategies, which I believe will define the next phase of therapeutic progress in PML and other neuroinfectious conditions.