396 NT-I7, a long-acting interleukin-7, promotes expansion of CD8 T cells and NK cells and immune activation in patients with newly diagnosed high-grade gliomas after chemoradiation

Abstract

BackgroundLymphopenia is common after chemoradiation for treatment of high-grade gliomas (HGG) and is associated with reduced survival.1 Interleukin-7 (IL-7) promotes T-cell maturation and proliferation and is inappropriately low in lymphopenic patients with HGG.2 We previously demonstrated that first-in-class long-acting IL-7, NT-I7 (efineptakin alfa), reverses lymphopenia and improves survival in murine glioma models.3 This study reports the correlative immune changes after NT-I7 treatment in patients with newly diagnosed HGG in a Phase I/II clinical trial.MethodsEnrolled patients had newly diagnosed HGG treated with concurrent radiotherapy (RT) and temozolomide (TMZ) plus adjuvant TMZ every 4 weeks. NT-I7 was administered intramuscularly 1 week after completion of RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I utilized the 3+3 design to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 patients in each arm. Immune profiling of patients from the Phase I study was performed with multiparametric flow cytometry and multiplex cytokine analysis.ResultsPhase I was completed with 19 patients. The most common adverse events were grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 µg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting the selection of MTD as 720 µg/kg. Preliminary analysis of Phase I subjects demonstrated dose-dependent increases in absolute lymphocyte count (ALC; 1.3X-4.1X fold increase from pre-therapy measurements) that peaked at week 4, before adjuvant TMZ. Flow cytometry analysis of peripheral blood showed a significant increase in the frequency of CD8+ T-cells, CD4+ T-cells, and CD56bright natural killer (NK) cells after NT-I7 administration. There was no change in B cell counts. Expression of the IL-7 receptor (CD127) was downregulated on most immune subsets within 1 week after NT-I7 administration and recovered to baseline by week 4. Serum cytokine analysis showed a rapid and significant increase in tumor necrosis factor (TNF), chemokine ligand 9 (CXCL9), and a trend to higher interferon-gamma (IFNγ), 1 week after NT-I7 administration.ConclusionsNT-I7 is well tolerated when administered after RT/TMZ for HGG patients. NT-I7 administration prompted an increase in ALC, especially cytotoxic T-cells and NK cells. We also observed rapid increases in key cytokines and chemokines, suggesting immune activation. These findings provide insight into the mechanism of action for NT-I7. Phase II enrollment and additional immune profiling correlates are ongoing.Trial RegistrationNCT03687957ReferencesMendez JS, Govindan A, Leong J, Gao F, Huang J, Campian JL. Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma. J Neurooncol 2016;127:329.Campian JL, Ye X, Gladstone DE, Ambady P, Nirschl TR, Borrello I, Golightly M, king KE, Holdhoff M, Karp J, Drake CG, Grossman SA. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neuro-Oncology 2015 1242. 2015;124:307–316.Ghosh S, Yan R, Thotala S, Jash A, Mahadevan A, Hu T, Lee B, Yang SH, Hallahan D, Chheda M, Thotala D, Campian J. 565 a novel long-acting interleukin-7 agonist, NT-I7, increases cytotoxic CD8+ T cells and enhances survival in mouse glioma models. J Immunother Cancer 2020;8(Suppl 3):A599–A599.Ethics ApprovalThis study was approved by Washington University’s ethics board (the Human Research Protection Office); approval number 201810185. Study participants provided written informed consent.

Advancements of Common Gamma-Chain Family Cytokines in Cancer Immunotherapy

“…Interim data has proven that NT-I7 is able to significantly boost ALC even in the presence of adjuvant chemotherapy. Interestingly, biomarker analysis showed that NT-I7 leads to the preferential increase of CD8 stem-cell memory T-cells (Tscm), a self-renewing subset with better anti-tumor activity compared to other memory CD8 T-cell subsets ( 57 ). In addition to testing NT-I7 monotherapy with standard of care in high-grade glioma patients, NT-I7 monotherapy is being tested in patients with locally recurrent squamous cell carcinoma of head and neck undergoing salvage surgery (NCT04588038) and Kaposi’s sarcoma with or without HIV (NCT04893018).…”