title: Enhancing Antitumor Immune Responses by Optimized Combinations of Cell-penetrating Peptide-based Vaccines and Adjuvants.
abstract: Cell penetrating peptides (CPPs) from the protein ZEBRA are promising candidates to exploit in therapeutic cancer vaccines, since they can transport antigenic cargos into dendritic cells and induce tumor-specific T cells. Employing CPPs for a given cancer indication will require engineering to include relevant tumor-associated epitopes, administration with an appropriate adjuvant, and testing for antitumor immunity. We assessed the importance of structural characteristics, efficiency of in vitro transduction of target cells, and choice of adjuvant in inducing the two key elements in antitumor immunity, CD4 and CD8 T cells, as well as control of tumor growth in vivo. Structural characteristics associated with CPP function varied according to CPP truncations and cargo epitope composition, and correlated with in vitro transduction efficiency. However, subsequent in vivo capacity to induce CD4 and CD8 T cells was not always predicted by in vitro results. We determined that the critical parameter for in vivo efficacy using aggressive mouse tumor models was the choice of adjuvant. Optimal pairing of a particular ZEBRA-CPP sequence and antigenic cargo together with adjuvant induced potent antitumor immunity. Our results highlight the irreplaceable role of in vivo testing of novel vaccine constructs together with adjuvants to select combinations for further development.
authors.affiliation: Amal Therapeutics, Geneva, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Belnoue
authors.affiliation: Center of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Wilma
authors.initials: W
authors.lastname: Di Berardino-Besson
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gaertner
authors.affiliation: Amal Therapeutics, Geneva, Switzerland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Carboni
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dunand-Sauthier
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cerini
authors.affiliation: Department of Cellular Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Else-Marit
authors.initials: EM
authors.lastname: Suso-Inderberg
authors.affiliation: Department of Cellular Therapy, Oslo University Hospital Radiumhospitalet, Oslo, Norway.|Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Wälchli
authors.affiliation: Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: König
authors.affiliation: Oncovir, Washington DC, USA.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
authors.affiliation: Center of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Dietrich
authors.affiliation: Center of Oncology, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Walker
authors.affiliation: Amal Therapeutics, Geneva, Switzerland.
authors.forename: Madiha
authors.initials: M
authors.lastname: Derouazi
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000276:immunology*; D002942:Circular Dichroism; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015534:Trans-Activators / Q000737:chemistry / Q000276:immunology; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; C063676:BZLF1 protein, Herpesvirus 4, Human; D019496:Cancer Vaccines; D057846:Cell-Penetrating Peptides; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D015534:Trans-Activators