Selinexor, A Selective Inhibitor Of Nuclear Export (Sine), Enhances The In Vivo Efficacy Of Checkpoint Blockade With Antibodies Targeting Ctla4 Or Pd-1/Pd-L1 In Melanoma

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LASelinexor is a SINE (Selective Inhibitor of Nuclear Export) compound that has been administered to u003e1000 cancer patients in Phase I and II trials to date, with evidence of efficacy and tolerability. This small molecule targets exportin-1 (XPO1), a key nuclear export protein with u003e200 cargo proteins which include both tumor suppressors and cell cycle modulators. As a result, selinexor blocks nuclear export of proteins including IκB, NFAT1c, STAT1 and STAT3, which regulate expression of the inhibitory T cell receptors CTLA4, PD1 and its ligand, PD-L1. We hypothesized that selinexor would upregulate T cell checkpoint molecule expression, and thereby enhance the anti-tumor activity of antibodies targeting PD-1/PD-L1 or CTLA4. Human (A375, CHL-1) and murine (B16F10) melanoma cell lines expressed high levels of PD-L1 protein at baseline, and PD-L1 expression was induced following selinexor treatment in numerous other tumor cell lines (including HCT-116, MDA-MB-468, MV-4-11, OVCAR-8, and PC-3). Examination of lymphocytes revealed that selinexor also increased expression of PD-1 and CTLA4 by ∼2-fold. Mice bearing syngeneic B16F10 melanoma tumors treated with selinexor (15 mg/kg 2 x weekly) and anti-CTLA4 (250 μg, 2 x weekly) demonstrated a significant reduction in tumor growth rate (p = 0.0065) while monotherapy had no significant effect on tumor growth. Similar results were obtained in mice bearing B16F10 melanoma treated with the combination of selinexor + anti-PD-1 (200 μg, 2 x weekly, p u003c 0.034) or selinexor + anti-PD-L1 (100-200 μg, 2 x weekly, p u003c 0.001). Importantly, no weight loss or signs of toxicity were evident in any in vivo study. Further immunophenotypic analyses have been completed in animals receiving selinexor alone or in combination with anti-PD-L1. In combination treated mice, we observed a significantly increased percentage of splenic NK cells (p ≤ 0.050), and a significantly increased percentage of splenic Th1 T cells (p≤0.011), all compared to vehicle treated mice. Interestingly, combining selinexor with anti-PD-L1 significantly decreased the percentage of splenocytes that expressed PD-L1 (pu003c0.001). These changes are indicative of increased anti-tumor immune activity; however, they were accompanied by significantly increased percentages of myeloid cell subsets in combination treated mice (p ≤ 0.050). The immunologic significance of this myeloid cell expansion is currently under investigation. These data indicate that the efficacy of selinexor may be enhanced by disrupting immune checkpoints in effector cells (T and NK cells). This provides data in support of novel, evidenced-based combinations involving immunotherapy with XPO1 inhibition that deserve further investigation for advanced cancer.Citation Format: Matthew R. Farren, Reena Shakya, Rebecca Hennessey, Thomas Mace, Jennifer Yang, Omar Elnaggar, Gregory Young, Yosef Landesman, Robert Carlson, Sivan Elloul, Marsha Crochiere, Christin Burd, Gregory B. Lesinski. Selinexor, a selective inhibitor of nuclear export (SINE), enhances the in vivo efficacy of checkpoint blockade with antibodies targeting CTLA4 or PD-1/PD-L1 in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2319.