title: Development of anti-tumor immunity against a non-immunogenic mammary carcinoma through in vivo somatic GM-CSF, IL-2, and HSVtk combination gene therapy.
abstract: Gene therapy for cancer using suicide genes such as the herpes simplex virus thymidine kinase gene (HSVtk) has been explored extensively in preclinical and clinical studies. We have improved the use of HSVtk by combining it with two cytokine genes encoding granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), and determined their additive/synergistic effects on tumor regression and inhibition of metastases in the non-immunogenic, spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV) were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a significant decrease in tumor growth and reduction of distant metastases with 25% of the tumors undergoing complete regression. When surgical excision of primary tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2 further enhanced long-term survival. A fraction of the treated mice developed anti-tumor immunity and survived a second challenge with 4T1. Functional analyses demonstrated infiltration of lymphocytes within the tumor and a strong tumor-specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals. These data indicate that the coexpression of GM-CSF and IL-2 can augment the effect of HSVtk suicide gene therapy.
authors.affiliation: Aventis Gencell, 3825 Bay Center Place, Hayward, California 94520, USA. Dirk_Brockstedt@cerus.com
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Melissa
authors.initials: M
authors.lastname: Diagana
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kimvan
authors.initials: K
authors.lastname: Tran
authors.forename: Nicole
authors.initials: N
authors.lastname: Belmar
authors.forename: Melinda
authors.initials: M
authors.lastname: Meier
authors.forename: Adrienne
authors.initials: A
authors.lastname: Yang
authors.forename: Florence
authors.initials: F
authors.lastname: Boissiere
authors.forename: Augustine
authors.initials: A
authors.lastname: Lin
authors.forename: Yawen
authors.initials: Y
authors.lastname: Chiang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D007376:Interleukin-2 / Q000235:genetics*; D008175:Lung Neoplasms / Q000556:secondary; D008214:Lymphocytes / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018139:Simplexvirus / Q000201:enzymology*; D013937:Thymidine Kinase / Q000235:genetics*; D013997:Time Factors; D019076:Transgenes
chemical_list: D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013937:Thymidine Kinase