Abstract 5536: Selinexor inhibits lymphoma-leukemia tumor progression directly and through activation of anti-cancer immune response

Abstract

Abstract Background: Selinexor is a Selective Inhibitor of Nuclear Export (SINE) compound that binds covalently to Exportin 1 (XPO1) and inhibits its nuclear export function, resulting in nuclear accumulation of tumor suppressor proteins (TSPs) including p53, pRB, and IκB-α. Selinexor was evaluated for improved survival in tumor-bearing mice with hematological malignancies using EL-4 (T cell lymphoma/leukemia) and C1498 (Acute myeloid leukemia) models. We hypothesized that selinexor increases survival by directly inducing tumor cell apoptosis and blocks immunosuppressive effects of myeloid derived suppressor cells (MDSCs). Methods: Mice were injected with 2×106 EL-4 or 1×106 C1498 cells intravenously followed by oral treatment with saline, vehicle, or different selinexor dosing schedules (5 mg/kg weekly (5), twice weekly on Wed and Fri (5 d1/3) or Mon and Fri (5 d1/5) or 10 mg/kg weekly (10). Selinexor was given by gavage. To examine the effect of selinexor on immune cells during tumor growth, Tumor bearing mice treated with vehicle or selinexor were euthanized at day 14 after tumor injection. Spleens were removed, single cell suspensions were isolated and the percentage of immune cells including MDSCs, regulatory T cells (Tregs) and the production of interferon gamma (IFN-γ) were analyzed by flow cytometry. Tumor bearing mice were monitored for survival in separate experiments. Results: Selinexor at the weekly 5 d1/3 and the 10 dosing significantly increased survival in mice injected with either tumor line. Whereas weekly 5 or 5 d1/5 dosing did not significant affect survival. Selinexor at weekly 10 dosing significantly reduced the population of polymorphonuclear MDSCs (PMN-MDSCs). Selinexor at 10, 5 d1/3 and 5/1/5 weekly dosing significantly increased IFN-γ production by CD8+ and CD4+ T cells when compared to vehicle. There were no differences in Tregs populations. Conclusions: These data demonstrate that different selinexor dosing and schedules have differential efficacy on survival in murine models of leukemia/lymphoma. Selinexor effects are dose and schedule dependent. We found that in contrast to the split dosing, the single weekly high dose of selinexor reduced splenic PMN-MDSC accumulation. While both dosing schedules increased the percentage of IFN-γ positive T cells in tumor bearing mice suggesting that selinexor’s anti-cancer activity is not limited only to direct cytotoxic or cytostatic tumor cells. These data support the concept that once weekly selinexor, at a higher dose (10 mg/kg (approximately 30 mg/m2) which is comparable to the clinical dose schedule (50-60 mg weekly) can modulate the immune system to target cancer cells and could be used alone or in combination with other immunotherapies to enhance the immune system. Citation Format: Hemn Mohammadpour, Yosef Landesman, Philip McCarthy. Selinexor inhibits lymphoma-leukemia tumor progression directly and through activation of anti-cancer immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5536.