title: Increasing vaccine potency through exosome antigen targeting.
abstract: While many tumor associated antigens (TAAs) have been identified in human cancers, efforts to develop efficient TAA "cancer vaccines" using classical vaccine approaches have been largely ineffective. Recently, a process to specifically target proteins to exosomes has been established which takes advantage of the ability of the factor V like C1C2 domain of lactadherin to specifically address proteins to exosomes. Using this approach, we hypothesized that TAAs could be targeted to exosomes to potentially increase their immunogenicity, as exosomes have been demonstrated to traffic to antigen presenting cells (APC). To investigate this possibility, we created adenoviral vectors expressing the extracellular domain (ECD) of two non-mutated TAAs often found in tumors of cancer patients, carcinoembryonic antigen (CEA) and HER2, and coupled them to the C1C2 domain of lactadherin. We found that these C1C2 fusion proteins had enhanced expression in exosomes in vitro. We saw significant improvement in antigen specific immune responses to each of these antigens in naïve and tolerant transgenic animal models and could further demonstrate significantly enhanced therapeutic anti-tumor effects in a human HER2+ transgenic animal model. These findings demonstrate that the mode of secretion and trafficking can influence the immunogenicity of different human TAAs, and may explain the lack of immunogenicity of non-mutated TAAs found in cancer patients. They suggest that exosomal targeting could enhance future anti-tumor vaccination protocols. This targeting exosome process could also be adapted for the development of more potent vaccines in some viral and parasitic diseases where the classical vaccine approach has demonstrated limitations.
authors: Duke Comprehensive Cancer Center, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors: Zachary C
authors: ZC
authors: Hartman
authors: Junping
authors: J
authors: Wei
authors: Oliver K
authors: OK
authors: Glass
authors: Hongtao
authors: H
authors: Guo
authors: Gangjun
authors: G
authors: Lei
authors: Xiao-Yi
authors: XY
authors: Yang
authors: Takuya
authors: T
authors: Osada
authors: Amy
authors: A
authors: Hobeika
authors: Alain
authors: A
authors: Delcayre
authors: Jean-Bernard
authors: JB
authors: Le Pecq
authors: Michael A
authors: MA
authors: Morse
authors: Timothy M
authors: TM
authors: Clay
authors: Herbert K
authors: HK
authors: Lyerly
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D055354:Exosomes / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology
chemical_list: D000954:Antigens, Surface; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D008894:Milk Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C098942:MFGE8 protein, human