title: Novel Treatment of Melanoma: Combined Parasite-Derived Peptide GK-1 and Anti-Programmed Death Ligand 1 Therapy.
abstract: Recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase pathway inhibitors, anticytotoxic T lymphocyte-associated antigen-4, and programmed cell death protein 1/programmed cell death ligand 1 (PD-L1) pathway-blocking antibodies, as well as combination strategies, all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with melanoma. One promising new treatment modality is based on the use of immunomodulatory monoclonal antibodies that enhance the function of components of the antitumor immune response such as T cells or block immunologic checkpoints that restrain effective antitumor immunity. Program death-1 receptor and its ligand, PD-L1, is a major mechanism by which a tumor suppresses T cell-mediated antitumor immune responses. Studies in mice have shown that GK-1, an 18 amino acid peptide from Taenia crassiceps cisticerci, has the potential to be used as a primary or adjuvant component for the treatment of cancers by stimulating proinflammatory cytokines. The authors hypothesized that treatment with GK-1 in combination with anti-PD-L1 will increase survival in mice bearing melanoma tumors. C57BL/6 mice were injected with B16-F10-luc2 cells and separated into four groups: control, GK-1, anti-PD-L1, and GK-1/anti-PD-L1. The tumor sizes were measured and monitored using calipers and bioluminescence. The GK-1 peptide in combination with anti-PD-L1 showed significantly longer survival (34 days) compared with the other groups (23-27 days). This means an increase; survival increased 47.82% in the mice treated with GK-1+anti-PD-L1, 21.7% in mice treated with GK-1 alone, and 6.08% in those mice treated with anti-PD-L1 only. Blood samples were collected at days 0, 14, and at euthanization or end of the experiment and monitored for cytokines using mouse-specific V-PLEX Proinflammatory Panel. A decrease in TNF-α, IL-4, IL-5, IL-6, and IL-10 serum levels was observed in the GK-1/anti-PD-L1 combination group that may explain the beneficial effects of the combination treatment in prolonging the life of mice bearing melanoma. The data indicate that GK-1/anti-PD-L1 combined therapy affectively increases survival and warrants further clinical investigations.
authors.affiliation: 1 Division of Hematology, Mayo Clinic , Rochester, Minnesota.|2 Division of Oncology, Mayo Clinic , Rochester, Minnesota.|3 Internal Medicine, School of Medicine at the Permian Basin, Texas Tech University Health Sciences Center , Odessa, Texas.
authors.forename: Jesus
authors.initials: J
authors.lastname: Vera-Aguilera
authors.affiliation: 4 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México , México City, Mexico .
authors.forename: Armando
authors.initials: A
authors.lastname: Perez-Torres
authors.affiliation: 3 Internal Medicine, School of Medicine at the Permian Basin, Texas Tech University Health Sciences Center , Odessa, Texas.
authors.forename: Diego
authors.initials: D
authors.lastname: Beltran
authors.affiliation: 5 Family Medicine, School of Medicine at the Permian Basin, Texas Tech University Health Sciences Center , Odessa, Texas.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Villanueva-Ramos
authors.affiliation: 6 Department of Pathology, Texas Tech University Health Sciences Center , Lubbock, Texas.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Wachtel
authors.affiliation: 7 Servicio de Gastrocirugía, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social , Ciudad de México, México .
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moreno-Aguilera
authors.affiliation: 4 Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México , México City, Mexico .
authors.forename: Carlos
authors.initials: C
authors.lastname: Vera-Aguilera
authors.affiliation: 3 Internal Medicine, School of Medicine at the Permian Basin, Texas Tech University Health Sciences Center , Odessa, Texas.
authors.forename: Gary
authors.initials: G
authors.lastname: Ventolini
authors.affiliation: 8 Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center , Lubbock, Texas.
authors.forename: Raul
authors.initials: R
authors.lastname: Martínez-Zaguilán
authors.affiliation: 8 Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center , Lubbock, Texas.
authors.forename: Souad R
authors.initials: SR
authors.lastname: Sennoune
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation; D049449:Luminescence; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010455:Peptides / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D013621:Taenia
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; D010455:Peptides; D010456:Peptides, Cyclic; C534327:cyclo(cysteinyl-glycyl-aspargyl-seryl-aspargyl-prolyl-lysyl-seryl-cysteine)
keywords: B16-F10-luc2; C57BL/6 mice; GK-1; melanoma; program death ligand 1 receptor