Development of anti-tumor immunity against a non-immunogenic mammary carcinoma through in vivo somatic GM-CSF, IL-2, and HSVtk combination gene therapy.
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.
Brockstedt
Dirk G
DG
Aventis Gencell, 3825 Bay Center Place, Hayward, California 94520, USA. Dirk_Brockstedt@cerus.com
Diagana
Melissa
M
Zhang
Ying
Y
Tran
Kimvan
K
Belmar
Nicole
N
Meier
Melinda
M
Yang
Adrienne
A
Boissiere
Florence
F
Lin
Augustine
A
Chiang
Yawen
Y
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
D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013937:Thymidine Kinase