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

Jian L. Campian, Subhajit Ghosh, Vaishali Kapoor, Ran Yan, Sukrutha Thotala, Arijita Jash, Tong Hu, Anita Mahadevan, Kasem Rifai, Logan Page, Byung Ha Lee, Sara Ferrando-Martinez, Alexandra A. Wolfarth, Se Hwan Yang, Dennis Hallahan, Milan G. Chheda, Dinesh Thotala

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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-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. 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-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. Results: GBM tumor–bearing mice treated with RTþNT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNg 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. Conclusions: 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).

Original languageEnglish
Pages (from-to)1229-1239
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number6
DOIs
StatePublished - Mar 15 2022

Fingerprint

Dive into the research topics of 'Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models'. Together they form a unique fingerprint.

Cite this