Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models

• Published in: Clinical cancer research Vol. 28; no. 6; pp. 1229 - 1239
• Main Authors: Campian, Jian L, Ghosh, Subhajit, Kapoor, Vaishali, Yan, Ran, Thotala, Sukrutha, Jash, Arijita, Hu, Tong, Mahadevan, Anita, Rifai, Kasem, Page, Logan, Lee, Byung Ha, Ferrando-Martinez, Sara, Wolfarth, Alexandra A, Yang, Se Hwan, Hallahan, Dennis, Chheda, Milan G, Thotala, Dinesh
• Format: Journal Article
• Language: English
• Published: United States 15-03-2022
• Subjects: Animals; Brain Neoplasms - pathology; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Glioblastoma; Glioma - pathology; Humans; Immunologic Factors - pharmacology; Interleukin-7; Lymphopenia; Mice; Mice, Inbred C57BL; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic - pathology; Temozolomide - pharmacology; Tumor Microenvironment
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-21-0947

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-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM.
C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (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 (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow.
GBM tumor-bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow.
In orthotopic glioma-bearing mice, NT-I7 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-I7 in patients with high-grade gliomas is ongoing (NCT03687957).