title: Cancer immunotherapy using Sindbis virus replicon particles encoding a VP22-antigen fusion.
abstract: Alphavirus vectors have emerged as a strategy for the development of cancer vaccines and gene therapy applications. The availability of a new packaging cell line (PCL), which is capable of generating alphavirus replicon particles without contamination from replication-competent virus, has advanced the field of vaccine development. This replication-defective vaccine vector has potential advantages over naked nucleic acid vaccines, such as increased efficiency of gene delivery and large-scale production. We have developed a new strategy to enhance nucleic acid vaccine potency by linking VP22, a herpes simplex virus type 1 (HSV-1) tegument protein, to a model antigen. This strategy facilitated the spread of linked E7 antigen to neighboring cells. In this study, we created a recombinant Sindbis virus (SIN)-based replicon particle encoding VP22 linked to a model tumor antigen, human papillomavirus type 16 (HPV-16) E7, using a stable SIN PCL. The linkage of VP22 to E7 in these SIN replicon particles resulted in a significant increase in the number of E7-specific CD8(+) T cell precursors and a strong antitumor effect against E7-expressing tumors in vaccinated C57BL/6 mice relative to wild-type E7 SIN replicon particles. Furthermore, a head-to-head comparison of VP22-E7-containing naked DNA, naked RNA replicons, or RNA replicon particle vaccines indicated that SINrep5-VP22/E7 replicon particles generated the most potent therapeutic antitumor effect. Our results indicated that the VP22 strategy used in the context of SIN replicon particles may facilitate the generation of a highly effective vaccine for widespread immunization.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Cheng
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: Keng-Fu
authors.initials: KF
authors.lastname: Hsu
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: John M
authors.initials: JM
authors.lastname: Polo
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Slater
authors.forename: Morris
authors.initials: M
authors.lastname: Ling
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D005260:Female; D018014:Gene Transfer Techniques; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D012093:Replicon / Q000235:genetics / Q000276:immunology*; D012845:Sindbis Virus / Q000276:immunology* / Q000502:physiology; D019444:Vaccines, DNA; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; C054582:ICP35 protein, Human herpesvirus 1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019444:Vaccines, DNA; D014764:Viral Proteins; C059731:oncogene protein E7, Human papillomavirus type 16