title: Costimulation enhances the active immunotherapy effect of recombinant anticancer vaccines.
abstract: Activation of T lymphocytes in the absence of a costimulatory signal can result in anergy or apoptotic cell death. Two molecules capable of providing a costimulatory signal, B7-1 (CD80) and B7-2 (CD86), have been shown to augment the immunogenicity of whole-tumor cell vaccines. To explore a potential role for costimulation in the design of recombinant anticancer vaccines, we used lacZ-transduced CT26 as an experimental tumor and beta-galactosidase (beta-gal) as the model tumor antigen. Attempts to augment the function of a recombinant vaccinia virus (rVV) expressing beta-gal by admixture with rVV expressing murine B7-1 were unsuccessful. However, a double recombinant vaccinia virus engineered to express both B7-1 and the model antigen beta-gal was capable of significantly reducing the number of pulmonary metastases when administered to mice bearing tumors established for 3 or 6 days. Most important, the double recombinant vaccinia virus prolonged the survival of tumor-bearing mice. These effects were antigen specific. The related costimulatory molecule B7-2 was found to have a similar, although less impressive enhancing effect on the function of a rVV expressing beta-gal. Thus, the addition of B7-1 and, to a lesser extent, B7-2 to a rVV encoding a model antigen significantly enhanced the therapeutic antitumor effects of these poxvirus-based, therapeutic anticancer vaccines.
authors.affiliation: Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Chamberlain
authors.forename: M W
authors.initials: MW
authors.lastname: Carroll
authors.forename: V
authors.initials: V
authors.lastname: Bronte
authors.forename: P
authors.initials: P
authors.lastname: Hwu
authors.forename: S
authors.initials: S
authors.lastname: Warren
authors.forename: J C
authors.initials: JC
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: B
authors.initials: B
authors.lastname: Moss
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: N P
authors.initials: NP
authors.lastname: Restifo
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen; D005260:Female; D016233:Immunotherapy, Active; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D014614:Vaccines, Synthetic / Q000276:immunology* / Q000627:therapeutic use; D014616:Vaccinia virus / Q000276:immunology / Q000378:metabolism*; D014765:Viral Vaccines / Q000276:immunology*; D001616:beta-Galactosidase / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D001616:beta-Galactosidase