title: Mechanisms of immunization against cancer using chimeric antigens.
abstract: Successful approaches to tumor immunotherapy must overcome the physiological state of tolerance of the immune system to self-tumor antigens. Immunization with appropriate variants of syngeneic antigens can achieve this. However, improvements in vaccine design are needed for efficient cancer immunotherapy. Here we explore nine different chimeric vaccine designs, in which the antigen of interest is expressed as an in-frame fusion with polypeptides that impact antigen processing or presentation. In DNA immunization experiments in mice, three of nine fusions elevated relevant CD8(+) T-cell responses and tumor protection relative to an unfused melanoma antigen. These fusions were: Escherichia coli outer membrane protein A (OmpA), Pseudomonas aeruginosa exotoxin A, and VP22 protein of herpes simplex virus-1. The gains of immunogenicity conferred by the latter two are independent of epitope presentation by major histocompatibility complex class II (MHC II). This finding has positive implications for immunotherapy in individuals with CD4(+) T-cell deficiencies. We present evidence that antigen instability is not a sine qua non condition for immunogenicity. Experiments using two additional melanoma antigens identified different optimal fusion partners, thereby indicating that the benefits of fusion vectors remain antigen specific. Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines.
authors.affiliation: The Swim Across America Laboratory, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Engelhorn
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Cailian
authors.initials: C
authors.lastname: Liu
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.forename: Gabriele A
authors.initials: GA
authors.lastname: Rizzuto
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cymerman
authors.forename: David N
authors.initials: DN
authors.lastname: Posnett
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019556:COS Cells; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology; D005098:Exotoxins / Q000235:genetics / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D015678:Viral Structural Proteins / Q000235:genetics / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000951:Antigens, Neoplasm; D001425:Bacterial Outer Membrane Proteins; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D029968:Escherichia coli Proteins; D005098:Exotoxins; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D015678:Viral Structural Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C073413:herpes simplex virus type 1 protein VP22; C078167:OMPA outer membrane proteins