title: A novel therapeutic regimen to eradicate established solid tumors with an effective induction of tumor-specific immunity.
abstract: OBJECTIVE
  The efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor-directed immune responses. In this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses.
  
  
  METHODS
  The Syrian hamster as an immune-competent model that supports replication of both adenovirus and vaccinia virus was evaluated in vitro and in vivo. The antitumor efficacy of either virus alone or sequential combination of the two viruses was examined in pancreatic and kidney cancer models. The functional mechanism of the regimen developed here was investigated by histopathology, immunohistochemistry staining, CTL assay, and T-cell depletion.
  
  
  RESULTS
  The Syrian hamster is a suitable model for assessment of oncolytic adenovirus and vaccinia virus. Three low doses of adenovirus followed by three low doses of vaccinia virus resulted in a superior antitumor efficacy to the reverse combination, or six doses of either virus alone, against pancreatic and kidney tumors in Syrian hamsters. A total of 62.5% of animals bearing either tumor type treated with the sequential combination became tumor-free, accompanied by the induction of effective tumor-specific immunity. This enhanced efficacy was ablated by CD3+ T-cell depletion but was not associated with humoral immunity against the viruses.
  
  
  CONCLUSIONS
  These findings show that sequential treatment of tumors with oncolytic adenovirus and vaccinia virus is a promising approach for cancer therapy and that T-cell responses play a critical role.
authors.affiliation: Sino-British Research Center for Molecular Oncology, Zhengzhou University, Zhengzhou, China.
authors.forename: James R
authors.initials: JR
authors.lastname: Tysome
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Li
authors.forename: Shengdian
authors.initials: S
authors.lastname: Wang
authors.forename: Pengju
authors.initials: P
authors.lastname: Wang
authors.forename: Dongling
authors.initials: D
authors.lastname: Gao
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Rathi
authors.initials: R
authors.lastname: Gangeswaran
authors.forename: Louisa S
authors.initials: LS
authors.lastname: Chard
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Ghassan
authors.initials: G
authors.lastname: Alusi
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Yaohe
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology / Q000502:physiology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D017209:Apoptosis; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D006801:Humans; D007121:Immunocompetence; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008647:Mesocricetus; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000821:virology; D047368:Tumor Burden; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014764:Viral Proteins