title: Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen generate long-term tumor-specific immunity.
abstract: Alphavirus vectors have emerged as a promising strategy for the development of cancer vaccines and gene therapy applications. In this study, we used the replication-defective vaccine vector SIN replicon particles from a new packaging cell line (PCL) to develop SIN replicon particles encoding calreticulin (CRT) linked to a model tumor antigen, human papillomavirus type 16 (HPV16) E7 protein. The linkage of CRT to E7 in SIN replicon particles resulted in a significant increase in E7-specific CD8(+) T-cell precursors and a strong antitumor effect against E7-expressing tumors in vaccinated mice. SINrep5-CRT/E7 replicon particles enhanced presentation of E7 through the major histocompatibility complex (MHC) class I pathway by infecting dendritic cells (DCs) directly and pulsing DCs with lysates of cells infected by SINrep5-CRT/E7 replicons. Vaccination of immunocompromised (BALB/c nu/nu) mice with SINrep5-CRT/E7 replicon particles also generated significant reduction of lung tumor nodules, suggesting that antiangiogenesis may contribute to the antitumor effect of SINrep5-CRT/E7 replicon particles. Furthermore, SINrep5-CRT/E7 replicon particles generated long-term in vivo tumor protection effects and antigen-specific memory immunities. We concluded that the CRT strategy used in the context of SIN replicon particles facilitated the generation of a highly effective vaccine for cancer prophylaxis and immunotherapy.
authors.affiliation: Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei.
authors.forename: W-F
authors.initials: WF
authors.lastname: Cheng
authors.forename: C-N
authors.initials: CN
authors.lastname: Lee
authors.forename: Y-N
authors.initials: YN
authors.lastname: Su
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chai
authors.forename: M-C
authors.initials: MC
authors.lastname: Chang
authors.forename: J M
authors.initials: JM
authors.lastname: Polo
authors.forename: C-F
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: C-Y
authors.initials: CY
authors.lastname: Hsieh
authors.forename: C-A
authors.initials: CA
authors.lastname: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037282:Calreticulin / Q000235:genetics*; D019496:Cancer Vaccines / Q000235:genetics*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000235:genetics; D012093:Replicon / Q000235:genetics; D012845:Sindbis Virus / Q000235:genetics*
chemical_list: D037282:Calreticulin; D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins