815 Combination with IL-15Rβγ superagonist, Nanrilkefusp alfa, enhances CAR T and BOXR T cell anti-tumor activity

BackgroundNanrilkefusp alfa (Nanril, SOT101) is an IL-15Rβγ superagonist that is comprised of the IL15 cytokine fused to the IL-15Rα and has demonstrated a favorable safety profile and encouraging efficacy signals as a monotherapy and in combination with KEYTRUDA® (pembrolizumab) in the Phase 1/1b AURELIO-03 trial. SOTIO’s BOXR cell therapy platform is designed to improve the functionality of CAR-T cells by incorporating novel transgenes that are co-expressed with tumor-targeting receptors to overcome resistance and improve the function of respective immune cells in the solid tumor microenvironment. Here we tested the combination of Nanril with CAR-T or BOXR-T cells in vitro and in in vivo efficacy studies.MethodsBOXR-T cells, CAR-T cells or untransduced (UTD) control T cells were treated with 0.1–1 nM Nanril for 3- 7 days and proliferation and memory phenotype were assessed by flow cytometry; RNAseq analysis was also performed. To assess in vitro cytotoxicity, T cells were pre-treated for three days with 0.1 nM Nanril and were then co-cultured with target cells and cell killing was monitored using Incucyte analysis. CAKI-1 and NCI-H1975 tumor models were used to assess CAR-T and BOXR-T cell anti-tumor activity in combination with Nanril where the Nanril dosing regimen was administered 7 days following CAR-T or BOXR-T cells treatment.ResultsNanril treatment induced proliferation in UTD, CAR-T and BOXR-T cells in a dose-dependent manner. Shifts in T cell memory populations were also observed with increasing Nanril concentration, resulting in a higher proportion of effector memory cells and subsequently improved in vitro cytotoxicity. RNAseq analysis findings were consistent with increased proliferation and differentiation with Nanril treatment. When tested in vivo, BOXR-T cells had superior anti-tumor activity compared to CAR-T cells and combination treatment with Nanril further improved both BOXR-T and CAR-T cell efficacy and increased peripheral blood expansion.ConclusionsThese data demonstrate that combination of Nanril with BOXR-T and CAR-T cells results in improved T cell function and anti-tumor activity in preclinical models. Combination of Nanril with T cell-based therapies may be a promising approach to increase efficacy in difficult-to-treat solid tumors.