title: MRP1-CD28 bi-specific oligonucleotide aptamers: target costimulation to drug-resistant melanoma cancer stem cells.
abstract: In this work we show a clinically feasible strategy to convert in situ the own tumor into an endogenous vaccine by coating the melanoma cancerous cells with CD28 costimulatory ligands. This therapeutic approach is aimed at targeting T-cell costimulation to chemotherapy-resistant tumors which are refractory and been considered as untreatable cancers. These tumors are usually defined by an enrichment of cancer stem cells and characterized by the higher expression of chemotherapy-resistant proteins. In this work we develop the first aptamer that targets chemotherapy-resistant tumors expressing MRP1 through a novel combinatorial peptide-cell SELEX. With the use of the MRP1 aptamer we engineer a MRP1-CD28 bivalent aptamer that is able to bind MRP1-expressing tumors and deliver the CD28 costimulatory signal to tumor-infiltrating lymphocytes. The bi-specific aptamer is able to enhance costimulation in chemotherapy-resistant tumors. Melanoma-bearing mice systemically treated with MRP1-CD28 bivalent aptamer show reduced growth, thus proving an improved mice survival.Besides, we have designed a technically feasible and translational whole-cell vaccine (Aptvax). Disaggregated cells from tumors can be directly decorated with costimulatory ligand aptamers to generate the vaccine Aptvax. CD28Aptvax made of irradiated tumor cells coated with the CD28-agonistic aptamer attached to MRP1 elicits a strong tumor- cell immune response against melanoma tumors reducing tumor growth.
authors.affiliation: Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.
authors.forename: Mario Martínez
authors.initials: MM
authors.lastname: Soldevilla
authors.affiliation: Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.|Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Casares
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.|Program Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Lasarte
authors.affiliation: Ross University School of Medicine, Roseau, Portsmouth, Commonwealth of Dominica.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.|Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Inoges
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.|Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Ascensión
authors.initials: A
authors.lastname: López-Díaz de Cerio
authors.affiliation: Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.|Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea, Pamplona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
mesh_terms: D000818:Animals; D017209:Apoptosis; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D018106:CD28 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D052157:Aptamers, Nucleotide; D018106:CD28 Antigens; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1
keywords: aptamer; cancer immunotherapy; costimutaltion; targeting