title: Immunotherapeutic intervention with oncolytic adenovirus in mouse mammary tumors.
abstract: The goal is to elucidate the immune modulating activity of an adenovirus (Adv) vector which showed therapeutic activity in human clinical trials. The oncolytic adenovirus (Adv/CD-TK) expressing two suicide genes was tested in two HER2/neu positive BALB/c mouse mammary tumor systems: rat neu-induced TUBO and human HER2-transfected D2F2/E2. Intra-tumoral (i.t.) Adv/CD-TK injection of TUBO tumor plus systemic prodrug therapy showed limited antitumor activity, not exceeding that by the virus itself. Antibody (Ab) to the virus was induced in Adv-/Luc-treated mice, to coincide with the loss of transgene expression. Low replication activity of adenoviruses in rodent cells may limit viral persistence. Host immunity against Adv or Adv-infected cells further mutes suicide gene activity. Treatment of TUBO tumors with Adv/CD-TK alone, however, induced neu-specific Ab responses. Treatment with Adv/CD-TK/GM (Adv/GM) that also expressed mouse granulocyte macrophage colony stimulating factor (GM-CSF), but without prodrug treatment, delayed tumor growth, enhanced anti-neu Ab production and conferred complete protection against secondary tumor challenge. D2F2/E2 tumor-bearing mice showed decreased tumor growth following i.t. Adv/GM treatment and they generated greater HER2-specific T-cell responses. These data suggest that i.t. injection of Adv itself induces immune reactivity to tumor-associated antigens and the encoded cytokine, GM-CSF, amplifies that immune response, resulting in tumor growth inhibition. Incorporation of suicide gene therapy did not improve the efficacy of Adv therapy in this mouse mammary tumor system. Oncolytic adenoviral therapy may be streamlined and improved by substituting the suicide genes with immune modulating genes to exploit tumor immunity for therapeutic benefit.
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Gibson
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Munns
authors.affiliation: Department of Radiation Oncology; Henry Ford Health System ; Detroit, MI USA.
authors.forename: Svend
authors.initials: S
authors.lastname: Freytag
authors.affiliation: Department of Radiation Oncology; Henry Ford Health System ; Detroit, MI USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Barton
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Veenstra
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Jayne
authors.initials: J
authors.lastname: Bissonette
authors.affiliation: Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
keywords: 5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; Ab, antibody; Adv, adenovirus; CD, cytosine deaminase; GCV, ganciclovir; GCV-MP, ganciclovir monophosphate; GFP, green fluorescent protein; GM-CSF, granulocyte macrophage colony stimulating factor; HER2/neu; HSV-1, herpes simplex virus 1; IFNγ, interferon gamma; IL-12, interleukin 12; IgG, immunoglobulin; MOI, multiplicity of infection; PFU, plaque-forming unit; PSA, prostate-specific antigen; SC, splenocytes; SFU, spot forming units; TK, thymidine kinase; adenovirus; granulocyte macrophage colony stimulating factor; i.p., intra-peritoneal; i.t., intra-tumoral; immunotherapy; mAb, monoclonal antibody; mouse mammary tumor; s.c., subcutaneous; suicide gene