title: Venezuelan equine encephalitis replicon immunization overcomes intrinsic tolerance and elicits effective anti-tumor immunity to the 'self' tumor-associated antigen, neu in a rat mammary tumor model.
abstract: Many tumor-associated antigens (TAAs) represent 'self' antigens and as such, are subject to the constraints of immunologic tolerance. There are significant barriers to eliciting anti-tumor immune responses of sufficient magnitude. We have taken advantage of a Venezuelan equine encephalitis-derived alphavirus replicon vector system with documented in vivo tropism for immune system dendritic cells. We have overcome the intrinsic tolerance to the 'self' TAA rat neu and elicited an effective anti-tumor immune response using this alphavirus replicon vector system and a designed target antigen in a rigorous rat mammary tumor model. We have demonstrated the capacity to generate 50% protection in tumor challenge experiments (p = 0.004) and we have confirmed the establishment of immunologic memory by both second tumor challenge and Winn Assay (p = 0.009). Minor antibody responses were identified and supported the establishment of T helper type 1 (Th1) anti-tumor immune responses by isotype. Animals surviving in excess of 300 days with established effective anti-tumor immunity showed no signs of autoimmune phenomena. Together these experiments support the establishment of T lymphocyte dependent, Th1-biased anti-tumor immune responses to a non-mutated 'self' TAA in an aggressive tumor model. Importantly, this tumor model is subject to the constraints of immunologic tolerance present in animals with normal developmental, temporal, and anatomical expression of a non-mutated TAA. These data support the continued development and potential clinical application of this alphaviral replicon vector system and the use of appropriately designed target antigen sequences for anti-tumor immunotherapy.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, School of Medicine and Molecular Biology and Biochemistry, University of California, Irvine, CA 97697-4060, USA. enelson@uci.edu
authors.forename: Edward L
authors.initials: EL
authors.lastname: Nelson
authors.forename: Darue
authors.initials: D
authors.lastname: Prieto
authors.forename: Terri G
authors.initials: TG
authors.lastname: Alexander
authors.forename: Peter
authors.initials: P
authors.lastname: Pushko
authors.forename: Loreen A
authors.initials: LA
authors.lastname: Lofts
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Rayner
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Kamrud
authors.forename: Bolyn
authors.initials: B
authors.lastname: Fralish
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D004195:Disease Models, Animal; D004666:Encephalitis Virus, Venezuelan Equine / Q000235:genetics*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007114:Immunization; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D012093:Replicon / Q000276:immunology*; D017634:Self Tolerance; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014614:Vaccines, Synthetic