title: The immunomodulatory, antitumor and antimetastatic responses of melanoma-bearing normal and alcoholic mice to sunitinib and ALT-803: a combinatorial treatment approach.
abstract: ALT-803, a novel IL-15/IL-15 receptor alpha complex, and the tyrosine kinase inhibitor, sunitinib, were examined for their single and combined effects on the growth of subcutaneous B16BL6 melanoma and on lymph node and lung metastasis. The study was conducted in immunocompetent C57BL/6 mice drinking water (Water mice) and in mice that chronically consumed alcohol (Alcohol mice), which are deficient in CD8(+) T cells. Sunitinib inhibited melanoma growth and was more effective in Alcohol mice. ALT-803 did not alter tumor growth or survival in Water or Alcohol mice. Combined ALT-803 and sunitinib inhibited melanoma growth and increased survival, and these effects were greater than sunitinib alone in Water mice. ALT-803 and alcohol independently suppressed lymph node and lung metastasis, whereas sunitinib alone or in combination with ALT-803 increased lymph node and lung metastasis in Water and Alcohol mice. Initially, ALT-803 increased IFN-γ-producing CD8(+)CD44(hi) memory T cells and CD8(+)CD44(hi)CD62L(lo) effector memory T cells and sunitinib decreased immunosuppressive MDSC and T regulatory cells (Treg). However, the impact of these treatments diminished with time. Subcutaneous tumors from Water mice showed increased numbers of CD8(+) T cells, CD8(+)CD44(hi) T cells, NK cells, and MDSC cells and decreased Treg cells after ALT-803 treatment.
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Kari A
authors.initials: KA
authors.lastname: Gaither
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Little
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Alisha A
authors.initials: AA
authors.lastname: McBride
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Savanna R
authors.initials: SR
authors.lastname: Garcia
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Kiranjot K
authors.initials: KK
authors.lastname: Brar
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Amity
authors.initials: A
authors.lastname: Platt
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA.
authors.forename: Faya
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA. meadows@wsu.edu.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Meadows
authors.affiliation: Department of Pharmaceutical Sciences and the Pharmaceutical Sciences Graduate Program, College of Pharmacy, Washington State University Spokane, PBS 323, P. O. Box 1495, Spokane, WA, 99210-1495, USA. hzhang@wsu.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000437:Alcoholism / Q000150:complications* / Q000276:immunology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000379:methods*; D005260:Female; D007211:Indoles / Q000008:administration & dosage; D008546:Melanoma, Experimental / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C582303:ALT-803; D007211:Indoles; D011506:Proteins; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; D000077210:Sunitinib
keywords: IL-15; Immunotherapy; Melanoma; Metastasis; Sunitinib