Abstract 1122: Selinexor synergizes with IL-12 to inhibit tumor growth in syngeneic mouse models of melanoma
Authors: Orr Shira , Henegar Leah , Walker Christopher J. , Wang Feng , Kashyap Trinayan , Maloof Marie , Martyn Kathleen , Kauffman Michael G. , Shacham Sharon , Landesman Yosef 
Published: June 2022

Background: Melanoma is the most deadly skin cancer and represents 4.6% of all cancers diagnosed within the US (American Cancer Society). Risk factors for melanoma are almost entirely related to pale skin color and sunburns. Selinexor is a clinically approved oral inhibitor of nuclear exportation protein Exportin 1 (XPO1/CRM1). In preclinical studies, selinexor significantly inhibited growth of A375 and CHL-1 human melanoma cell lines in vivo at well tolerated doses (Yang et al. 2014). Interleukin 12 (IL-12) is a cytokine produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells in response to antigenic stimulation. IL-12 drives the differentiation of T-cells into T helper (Th1) cells, in addition to stimulating T-cell and NK cell activity, specifically through the activation of interferon-γ (IFN-γ). IL-12 exerts antitumor activity through IFN-γ-dependent and independent mechanisms, which include modulation of the immune system and anti-angiogenesis (Zhang et al. 2016). The objective of this study was to compare the impact and scheduling of recombinant mouse IL-12 alone and in combination with selinexor on the growth of murine B16F10 melanoma cells grown as subcutaneous tumors in C57B/6 mice.

Methods: Sixty, 6-7 weeks old female C57B/6 mice were inoculated subcutaneously in the left flank with 1 x 105 B16F10 cells. Treatment was initiated when the tumors reached a mean volume of 100 mm3 (standard deviation ± 6.3 mm3). Mice were allocated to 6 groups of 10 such that mean tumor volume in each group was within the range of 11.8 to 13.4 mm3, then treated with: oral selinexor (10mg/kg, twice weekly on day 0 and 2) combined with a pre-dose of subcutaneous IL-12 (1µg/kg, once weekly on day -2); selinexor with post-dose IL-12 (1µg/kg, once weekly on day 3); selinexor alone; IL-12 alone (day -2); IL-12 alone (day 3); or vehicle. Animal weight was recorded daily, and tumors were measured 3 days a week to record percent of tumor growth inhibition (%TGI).

Results: Both selinexor and IL-12 demonstrated single agent activity against B16F10 tumor in vivo. All treatment groups showed significant tumor growth inhibition as compared to vehicle. The group receiving selinexor with pre-dose IL-12 showed the largest tumor inhibition (%TGI=92%). Significant weight loss compared to vehicle occurred only in the single agent selinexor group (p=0.039).

Conclusions: Synergistic anti-cancer activity of selinexor and IL-12 warrants further clinical investigation. Further mechanistic studies to understand the effects of IL-12 priming on increasing the effectiveness of selinexor will be undertaken.

Citation Format: Shira Orr, Leah Henegar, Christopher J. Walker, Feng Wang, Trinayan Kashyap, Marie Maloof, Kathleen Martyn, Michael G. Kauffman, Sharon Shacham, Yosef Landesman. Selinexor synergizes with IL-12 to inhibit tumor growth in syngeneic mouse models of melanoma [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 1122.