Tumor eradication by hetIL-15 locoregional therapy correlates with an induced intratumoral CD103intCD11b+ dendritic cell population

Stellas, Dimitris; Karaliota, Sevasti; Stravokefalou, Vasiliki; Angel, Matthew; Nagy, Bethany A.; Goldfarbmuren, K.C.; Bergamaschi, Cristina; Felber, Barbara K.; Pavlakis, George N.

doi:10.1016/j.celrep.2023.112501

Cited by 4 publications

(1 citation statement)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 37 It has been argued that systemic administration of IL-15 formulation may not be sufficient to overcome the negative effects of tumor microenvironment, whereas local delivery achieves higher concentrations of cytokine and better therapeutic results. 26 One mechanism contributing to suppressive tumor microenvironment is based on the induction of checkpoint molecules, including PD-1, on CD8+ T cells. 37 Therefore, various clinical trials have been initiated to investigate the safety and efficacy of IL-15-based combinations with different ICIs are currently being investigated in several phase I clinical trials.…”

Section: Discussionmentioning

confidence: 99%

First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors

Leidner,

Conlon,

McNeel

et al. 2023

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundPreclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors.MethodsThis phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1–sensitive or anti-PD-1–resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase.ResultsAs of February 17, 2020, 83 patients (median age: 63 years; range: 28–85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1–2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3–4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1–sensitive and 20% (5/25) in the anti-PD-1–resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments.ConclusionsNIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs.Trial registration numberNCT02452268.

show abstract

Section: Discussionmentioning

confidence: 99%