Abstract 1345: Antitumor and antimetastatic response of melanoma-bearing normal and alcoholic mice to Sunitinib and ALT-803 treatment
Authors: Gaither Kari A. , Little Alexander A. , McBride Alisha A. , Castillo Savanna , Brar Kiran K. , Platt Amity , Zhu Zhaohui , Zhang Faya , Luong Dung , Zhang Hui , Meadows Gary G. 
Published: August 2015

Abstract
Chronic alcohol consumption (CAC) is a risk factor for melanoma as well as other cancers and can result in decreased patient survival. We previously showed that CAC increases the percentage of IFN-γ-producing CD8+ T cells exhibiting a memory phenotype (CD44hi) in the early stage of primary B16BL6 melanoma development; however, these cells rapidly decrease with continued tumor growth. CAC also results in decreased cells producing IL-15, a cytokine essential for sustained proliferation and survival of CD8+ T cells. In addition, myeloid derived suppressor cells (MDSC), which can inhibit CD8+ T cell proliferation and activation and thus suppress antitumor immune responses, also increase in the blood of melanoma-bearing mice during CAC. Herein, we examined the single and combined effects of ALT-803, a novel IL-15/IL-15 receptor alpha complex designed to increase CD8+ T cell proliferation and activation and Sunitinib, known to inhibit MDSC, on primary melanoma growth and metastasis in female C57BL/6 mice inoculated s.c. with B16BL6 melanoma and given continuous water or 20% w/v alcohol. Both drugs are being evaluated separately in human melanoma clinical trials. ALT-803 did not inhibit primary tumor growth or increase survival when given weekly at a dose of 0.2 mg/kg but did inhibit tumor growth and increase survival at a dosage of 1.5-2.0 mg/kg. Sunitinib (40 mg/kg daily) given alone and in combination with ALT-803 inhibited tumor growth compared to untreated water and alcohol controls. Sunitinib had a greater effect on tumor growth and final tumor weight in alcohol drinking mice compared to water drinking mice. Sunitinib increased survival and in combination with ALT-803 extended survival further. MDSC, which increased with tumor growth in untreated mice, were initially suppressed by Sunitinib; however, continued tumor growth overcame the initial suppressive effect. ALT-803 increased levels of CD8+ T cells, CD8+CD44hi T cells, and IFN-γ-producing CD8+ T cells. This effect decreased with continued tumor growth. ALT-803 inhibited and Sunitinib increased lymph node and lung metastasis in mice inoculated s.c. with melanoma. The Sunitinib effect on metastasis was not abrogated in combination with ALT-803. Further studies to investigate the mechanisms associated with these findings are warranted. Supported by NIH Grants K05AA017149 and R21AA022098 to GGM and HZ and NSF pre-doctoral fellowship DGE-1347973 to KAG.
Citation Format: Kari A. Gaither, Alexander A. Little, Alisha A. McBride, Savanna Castillo, Kiran K. Brar, Amity Platt, Zhaohui Zhu, Faya Zhang, Dung Luong, Hui Zhang, Gary G. Meadows. Antitumor and antimetastatic response of melanoma-bearing normal and alcoholic mice to Sunitinib and ALT-803 treatment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1345. doi:10.1158/1538-7445.AM2015-1345