title: Targeting inhibition of Foxp3 by a CD28 2'-Fluro oligonucleotide aptamer conjugated to P60-peptide enhances active cancer immunotherapy.
abstract: The specific inhibition of Treg function has long been a major technical challenge in cancer immunotherapy. So far no single cell-surface marker has been identified that could be used to distinguish Treg cells from other lymphocytes. The only available specific marker mostly expressed in Treg is Foxp3, which is an intracellular transcription factor. A targeting molecule able to penetrate the membrane and inhibit Foxp3 within the cell is needed. P60-peptide is able to do that, but due to lack of target specificity, the doses are extremely high. In this study we have shown as a proof of concept that P60 Foxp3 inhibitor peptide can be conjugated with a CD28 targeting aptamer to deliver the peptide to CD28-expressing cells. The AptCD28-P60 construct is a clinically feasible reagent that improves the efficacy of the unconjugated P60 peptide very significantly. This approach was used to inhibit Treg function in a vaccination context, and it has shown a significant improvement in the induced immune response, entailing a lower tumor load in an antigen-specific cancer vaccine protocol.
authors.affiliation: Program Immunology and Immunotherapy, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lozano
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea 3, 31008, Pamplona, Spain; Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain.
authors.forename: Mario Martínez
authors.initials: MM
authors.lastname: Soldevilla
authors.affiliation: Program Immunology and Immunotherapy, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea 3, 31008, 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 3, 31008, Pamplona, Spain; Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Villanueva
authors.affiliation: Ross University School of Medicine, PO Box 266, Roseau, Portsmouth, Dominica.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bendandi
authors.affiliation: Program Immunology and Immunotherapy, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea 3, 31008, Pamplona, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Lasarte
authors.affiliation: Instituto de Investigación Sanitaria de Navarra (IDISNA), Recinto de Complejo Hospitalario de Navarra, Irunlarrea 3, 31008, Pamplona, Spain; Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Medica Aplicada (CIMA), Pamplona, Avenida Pio XII 55, 31008, Pamplona, Spain. Electronic address: fpasordri@unav.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pastor
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D014611:Vaccination
chemical_list: D052157:Aptamers, Nucleotide; D018106:CD28 Antigens; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010455:Peptides
keywords: Aptamer; FOXP3; Immunotherapy; Therapeutic; Treg