TY - JOUR
T1 - Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models
AU - Campian, Jian L.
AU - Ghosh, Subhajit
AU - Kapoor, Vaishali
AU - Yan, Ran
AU - Thotala, Sukrutha
AU - Jash, Arijita
AU - Hu, Tong
AU - Mahadevan, Anita
AU - Rifai, Kasem
AU - Page, Logan
AU - Lee, Byung Ha
AU - Ferrando-Martinez, Sara
AU - Wolfarth, Alexandra A.
AU - Yang, Se Hwan
AU - Hallahan, Dennis
AU - Chheda, Milan G.
AU - Thotala, Dinesh
N1 - Funding Information:
This work was supported by NeoImmuneTech, Inc., Department of Radiation Oncology Startup Funds (D. Thotala), National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award number R01 NS117149 (to M.G. Chheda), Alvin J. Siteman Cancer Research Fund (M.G. Chheda), and the Alvin J. Siteman Cancer Center Siteman Investment Program through funding from The Foundation for Barnes-Jewish Hospital and the Barnard Trust (J.L. Campian and M.G. Chheda). The authors are grateful to Sachendra S. Bais for assisting with cell culture and mouse implantations. They thank the Department of Radiation Oncology for shared resources and animal facilities. They also thank Katie Duncan and Julie Prior at Small-Animal Cancer Imaging—Siteman Cancer Center Washington University School of Medicine for help with BLI.
Funding Information:
J.L. Campian reports grants and other support from NeoImmuneTech during the conduct of the study, as well as other support from Incyte, Merck, Ipsen, and NeoImmuneTech outside the submitted work. B.H. Lee, S. Ferrando-Martinez, and A.A. Wolfarth report other support from NeoImmuneTech, Inc., during the conduct of the study and outside the submitted work. M.G. Chheda reports grants from NeoImmuneTech, National Institutes of Health, Alvin J. Siteman Cancer Center, and The Foundation for Barnes-Jewish Hospital and the Barnard Trust during the conduct of the study, as well as other support from Orbus Therapeutics, Incyte, Merck, and UpToDate outside the submitted work; in addition, M. G. Chheda has a patent for Zika virus strains for the treatment of GBM pending. No disclosures were reported by the other authors.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/3/15
Y1 - 2022/3/15
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85126388698&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0947
DO - 10.1158/1078-0432.CCR-21-0947
M3 - Article
C2 - 35031547
AN - SCOPUS:85126388698
SN - 1078-0432
VL - 28
SP - 1229
EP - 1239
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -