NT-I7, a long-acting interleukin-7, increases lymphocyte counts and induces CD8+ T cell clonotype expansion in patients with newly diagnosed high-grade gliomas

Purpose: Standard care for high-grade gliomas (HGG) involves maximal surgical resection followed by radiation and temozolomide. Postoperative adjuvant therapy frequently causes lymphopenia, which is associated with poor prognosis. Interleukin-7 (IL-7) is essential for lymphocyte development, homeostasis, and survival. NT-I7 (efineptakin alfa), a long-acting recombinant IL-7, reverses lymphopenia and improves survival in murine glioma models. However, the safety, maximum tolerated dose (MTD), and impact of NT-I7 on immune cells in HGG patients remain unknown. Experimental Design: We conducted a Phase I trial (NCT03687957) examining the MTD and effect of NT-I7 on lymphocytes in patients with newly diagnosed HGG. The primary endpoint was dose-limiting toxicity; secondary endpoints included ALC changes over time, overall response, progression free survival (PFS) and overall survival (OS). Exploratory endpoints included immune profiling at different timepoints using single-cell RNA sequencing (scRNA-seq) in a subset of patients. Results: NT-I7 was well tolerated with a MTD of 720 µg/kg. Moreover, NT-I7 significantly increased absolute lymphocyte counts for over 12 weeks in duration. Early elevations in CD4+, CD8+ T cells and NK cells further coincided with increased TNF and CXCL9 cytokine levels. Comprehensive immune profiling of peripheral blood T cells revealed selective clonotype expansion within CD8⁺, but not CD4⁺, T cells following NT-I7 administration. Finally, a subset of our patients with MGMT promoter–unmethylated glioblastoma (GBM), which are typically associated with a poorer prognosis, demonstrated promising clinical responses. Conclusions: NT-I7 has the potential to maintain and increase lymphocyte counts in HGG patients and warrants further investigation, particularly in combination with immune-based therapies.