Long-Acting Recombinant Human Interleukin-7, NT-17, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models

Purpose: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-17 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-17 prevents systemic lymphopenia and improves survival in mouse models of GBM. Experimental Design: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day x 5 days), TMZ (33 mg/kg/day x 5 days), and/or NT-17 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (T-reg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. Results: GBM tumor-bearing mice treated with RT+NT-17 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFN gamma production, and decreased T-regs in the tumor which was associated with a significant increase in survival. NT-17 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-17. Furthermore, NT-17 treatment decreased progenitor cells in the bone marrow. Conclusions: In orthotopic glioma-bearing mice, NT-17 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-17 in patients with high-grade gliomas is ongoing (NCT03687957).

Automated summary

In this study, NT-17 was found to prevent systemic lymphopenia in GBM patients receiving radiotherapy and temozolomide, while improving survival. Furthermore, NT-17 increased cytotoxic CD8 T lymphocytes in lymphoid organs and tumor.