2040 Background: High-grade gliomas (HGG) patients can develop prolonged lymphopenia after standard radiation therapy (RT) and temozolomide (TMZ), which has been shown to correlate with worse survival. Interleukin-7 (IL-7) level, a cytokine that stimulates T-cell homeostasis and proliferation, is disproportionally low in HGG patients with lymphopenia. NT-I7 (efineptakin alfa) is the first-in-class long-acting recombinant human IL-7 that supports proliferation and survival of CD4+ and CD8+ T-cells in humans and mice. Our previous study demonstrated that NT-I7 could correct lymphopenia and improve the survival of orthotopic murine glioma models. The current study aims to examine the safety of administering NT-17 after chemoradiotherapy to HGG patients and its effect on systemic absolute lymphocyte count (ALC). Methods: All patients with newly diagnosed HGG who have completed concurrent RT/TMZ were considered eligible, regardless of ALC. NT-I7 was initially administered intramuscularly within 1 week after completion of RT/TMZ and then every 12 weeks for up to 4 doses. Patients also received adjuvant TMZ 4 weeks after RT/TMZ. The phase I study tested 6 dose levels of NT-I7, including 60, 120, 240, 540, 720, and 960 mcg/kg, adopting an accelerated phase for the first two doses followed by the standard 3+3 design. The primary endpoint was the safety of NT-I7 in HGG. The Phase II study is a double-blinded randomized study with 10 patients per arm to evaluate the effect of NT-I7 on ALC compared to placebo controls. Blood samples at baseline and during the NT-I7 administrations will be collected for immune profiling by CyTOF, single-cell RNA-sequencing, and cytokine analysis. Results: Phase I was completed with 19 patients (2 anaplastic oligodendrogliomas and 17 glioblastomas), with a median age of 58 years (range: 25-78). Median baseline ALC was 1000 cells/mm3 before NT-I7 administration, and the median baseline dexamethasone use was 0 mg/day (range 0-12). The median number of NT-I7 doses given was 2 (range: 2-4). Treatment-related adverse events (TRAEs) were dose-dependent. The most common TRAEs were grade 1/2 injection site reactions (50%), flu-like symptoms (26%), rash (21%), and fatigue (21%). Two patients had dose-limiting toxicities at 960 mcg/kg (a grade 3 elevated alanine aminotransferase and a grade 3 muscle pain). ALC was increased in a dose-dependent manner with a range of 1.3 – 4.1 fold at week 4 after NT-I7 injection and lasted up to 12 weeks. Thus, 720 mcg/kg was identified as the recommended phase II dose (RP2D). Conclusions: NT-I7 is well tolerated for HGG patients after chemoradiotherapy and has a RP2D of 720 mcg/kg. Immune profiling and cytokine analysis are ongoing and will be updated. The Phase II randomized study to evaluate the effect of NT-I7 vs placebo on ALC and survival is ongoing. Clinical trial information: NCT03687957.
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.
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