A low lymphocyte count puts immune‐compromised patients at risk of mortality. hIL‐7‐hyFc is a homodimeric interleukin‐7 (IL‐7), a potent T‐cell amplifier, fused to the hybridizing IgD/IgG4 immunoglobulin domain. We performed a randomized, double‐blind, placebo‐controlled, dose‐escalation, phase I study to assess the pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles of hIL‐7‐hyFc administered s.c. and i.m. to healthy volunteers. Thirty subjects randomly received hIL‐7‐hyFc or its matching placebo in an 8:2 ratio at 20, 60 μg/kg s.c., or 60 μg/kg i.m. The hIL‐7‐hyFc was slowly absorbed and its terminal half‐life was 63.26 hours after i.m. administration. The hIL‐7‐hyFc increased absolute lymphocyte count, mostly in T‐cells, which peaked 3 weeks after administration and then lasted for several additional weeks. The hIL‐7‐hyFc was well‐tolerated after a single s.c. and i.m. administration. Injection site reaction was the most common treatment‐emergent adverse event, which resolved spontaneously without treatment. The hIL‐7‐hyFc can be developed into a beneficial treatment option for patients with compromised T‐cell immunity. This trial was registered at http://www.clinicaltrials.gov as #NCT02860715.

Interleukin-7 (IL-7) is an essential cytokine for T-cell homeostatic proliferation and maintenance. Clinical studies have shown the potential benefits of IL-7 therapy in various diseases associated with lymphopenia. However, the kinetics of the T-cell response to a single administration of IL-7 in humans have not been fully elucidated. Here, we investigated the effects of Fc-fused long-acting recombinant human IL-7 (hIL-7-hyFc, efineptakin alfa) on lymphocytes in healthy adults after a single subcutaneous or intramuscular administration. Administration of hIL-7-hyFc increased the CD8+ and CD4+ T-cell numbers up to 2.5-fold, with corresponding upregulation of Ki-67 and Bcl-2 expression, peaking at day 3 or 7. Regulatory T cells did not expand. Among CD8+ and CD4+ T cells, all T-cell subsets (TN, TEM, TCM, TEMRA, and TSCM) increased for 56 days. The TCR repertoire diversity of naïve CD8+ and CD4+ T cells was increased by hIL-7-hyFc, while the memory T-cell subsets did not differ between D56 and D0. Transcriptomic analysis revealed that hIL-7-hyFc induced robust T-cell expansion without changes in gene expression profiles associated with T-cell functions or genes related to T-cell exhaustion, senescence, and anergy. The effector functions of antigen-specific CD8+ T cells were preserved after hIL-7-hyFc administration. Our results suggest that hIL-7-hyFc administration induced a sustained increase in the numbers of CD8+ and CD4+ T cells, but not regulatory T cells, without qualitative changes. These results support the potential of hIL-7-hyFc as a treatment for patients with compromised T-cell immunity or as a vaccine adjuvant.

Objectives GX-H9 is a long-acting form of recombinant human GH under clinical development for both adults and children with GHD. In this report, 24-month efficacy and safety of once weekly and every other week (EOW) administration of GX-H9 were evaluated, in addition to Genotropin® switch-ability to GX-H9 after 12-month of treatment. Methods Subjects were randomly assigned to receive either one of three doses of GX-H9 (0.8 mg/kg/week, 1.2 mg/kg/week or 2.4 mg/kg every other week) or 0.03 mg/kg/day of Genotropin®. Treatment duration is 24-month for all patients in GX-H9 arms while patients in Genotropin® arm were re-randomized to one of three doses of GX-H9 at the completion of the first 12-month of treatment. Doses of GX-H9 were adjusted throughout the treatment period whenever necessary, based on IGF-1 levels. Results Out of 56 randomized, 54 received either GX-H9 or Genotropin®. Fifty subjects completed the 12-month treatment period. Of 50, 45 subjects completed the next 12-month, comprising 33 patients from GX-H9 and 12 patients who switched from Genotropin®. First year/second year mean±SD annualized height velocity (aHV) for 0.8 mg/kg/week, 1.2 mg/kg/week or 2.4 mg/kg every other week of GX-H9 were 10.50±2.54/9.14±1.96, 11.76±1.96/9.88±1.92 and 11.03±2.92/9.72±1.90 cm/year, respectively. First year mean±SD aHV for Genotropin® was 9.14±3.09 cm/year. Patients switched to one of the three doses of GX-H9 in the second year showed comparable aHV in the second year (8.73±2.69/7.60±0.90/9.13±1.07 cm/year for 0.8 mg/kg/week, 1.2 mg/kg/week and 2.4 mg/kg/EOW GX-H9, respectively). No significant slow-down of the growth was observed in the second year from patients who received GX-H9 throughout and patients who switched from Genotropin®. Mean change in height SDS after 12 months/24 months of GX-H9 treatment throughout from baseline treatment improved continuously (+1.10/+1.61 and +1.31/+1.89 and +1.15/+1.69 for 0.8 mg/kg/week, 1.2 mg/kg/week and 2.4 mg/kg EOW GX-H9, respectively). First year mean change in height SDS for Genotropin® was +0.92 SDS, and showed comparable improvement in height SDS after switching to GX-H9 weekly arms (+0.76 and +0.79 SDS for 0.8 mg/kg/week and 1.2 mg/kg/week, respectively). Most treatment-emergent adverse events were evaluated as unrelated to the study drug and were mild or moderate in severity. No new safety concerns were observed throughout 24 months of long-term GX-H9 treatment or after switching to GX-H9 from Genotropin®.Conclusions Growth response and safety profile of GX-H9 in children with GHD is comparable to those of daily GH, achieving robust growth rates after 24-month treatment. Subjects switched from Genotropin® in the second year, also showed substantial catch-up growth indicated by improvement in height SDS. GX-H9 has a unique potential to be a convenient long-term GH providing not only weekly but also twice-monthly treatment.

Purpose Addressing lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin‐7 (IL‐7) is necessary for proliferation of lymphocytes and to increase total lymphocyte count (TLC), IL‐7 therapy has been attempted in various cancers. Here, we describe the clinical results of treatment of recurrent glioblastoma (GBM) with a long‐acting engineered version of recombinant human IL‐7 (rhIL‐7‐hyFc). Methods This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Primary outcomes were safety profile and TLC. Secondary outcomes were overall survival (OS) and progression‐free survival (PFS). Results Among the 18 patients enrolled, 10 received rhIL‐7‐hyFc with temozolomide, 5 received rhIL‐7‐hyFc with bevacizumab, 1 received rhIL‐7‐hyFc with PCV chemotherapy, and 2 received rhIL‐7‐hyFc alone. Mean TLC of the enrolled patients after the first rhIL‐7‐hyFc treatment increased significantly from 1131 cells/mm 3 (330–2989) at baseline to 4356 cells/mm 3 (661–22,661). Higher TLCs were maintained while rhIL‐7‐hyFc was repeatedly administered. Median OS and PFS were 378 days (107–864 days) and 231 days (55–726 days), respectively. Conclusion Our study reports that IL‐7 immunotherapy can restore and maintain TLC during treatment with various salvage chemotherapies in recurrent GBM patients without serious toxicity.

1081 Background: GX-I7 (efineptakin alfa) is a hybrid Fc-fused long-acting recombinant human IL-7 which plays an essential role in the development and homeostasis of T-cells. GX-I7 can potentially enhance the anti-tumor effect of pembrolizumab via induction of T-cell activity. Here, we report results of phase 1b/2 study of GX-I7 plus pembrolizumab in patients with R/R mTNBC. Methods: Eligible patients had R/R mTNBC that failed up to 3rd lines of chemotherapy in the metastatic setting. Phase 1b patients received GX-I7 in 5 dose levels ranging from 360 µg/kg to 1,440 µg/kg every 9 (Q9W) or 12 (Q12W) weeks plus pembrolizumab 200 mg Q3W (n=51). Phase 2 is an expansion cohort where 33 patients were treated with the recommended phase 2 dose (RP2D). The primary objective was to determine the RP2D for phase 1b and to assess the objective response rate (ORR) for phase 2. Results: The study included 84 patients (phase 1b, n=51; phase 2, n=33) and 53.6% (45/84) of patients have received 2nd to 3rd lines of previous therapy. In phase 1b, one dose-limiting toxicity (DLT; grade 3 skin rash) was reported in the 1,440 µg/kg cohort and GX-I7 1,200 µg/kg Q9W was selected as RP2D. The ORRs were 15.7% [95% confidence interval (CI): 7.0 – 28.6] for phase 1b (n=51) and 21.2% [95% CI: 9.0 – 38.9] for phase 2 (n=33). Median PFS was 2.4 months (95% CI: 2.1 – 2.7) at the median follow-up of 10.4 months for all patients combined (n=84). GX-I7 induced up to 3.6-fold (range 1.2 – 8.1) increase in absolute lymphocyte counts (including CD4+ and CD8+ T cell) in all dose levels. The most common treatment-related adverse events (AEs) of any grade were injection site reaction (50.0%), ALT increased (39.3%), pyrexia (38.1%) and rash (35.7%). The additional correlative study data will be presented. Conclusions: GX-I7 in combination with pembrolizumab demonstrated a manageable safety profile with promising anti-tumor activity in patients with R/R metastatic TNBC. Clinical trial information: NCT03752723. [Table: see text]