Eradication of hepatoma and colon cancer in mice with Flt3L gene therapy in combination with 5-FU

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2007-10, Vol.56 (10), p.1605-1613
• Main Authors: Hou, Sheng, Kou, Geng, Fan, Xiaoqiang, Wang, Hao, Qian, Weizhu, Zhang, Dapeng, Li, Bohua, Dai, Jianxin, Zhao, Jian, Ma, Jing, Li, Jing, Lin, Birong, Wu, Mengchao, Guo, Yajun
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviruses; Adoptive Transfer; Animals; Antigen-presenting cells; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Bone marrow; Bone Marrow - drug effects; Bone tumors; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; CD3 antigen; CD8 antigen; Cells; Chemotherapy; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Colonic Neoplasms - therapy; Colorectal cancer; Combined Modality Therapy; Cytomegalovirus; Cytomegalovirus - genetics; Drug dosages; FLT3L protein; Fluorouracil - adverse effects; Fluorouracil - therapeutic use; Gene therapy; Genetic Therapy; Genetic Vectors - genetics; Hematopoiesis - drug effects; Hepatoma; Hypotheses; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Lymphocytes T; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Natural killer cells; Original; Promoter Regions, Genetic; Radiation therapy; Spleen - immunology; Tumors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-007-0306-3

We developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter to investigate the biological efficacy of Flt3L in combination with chemotherapeutical drug, 5-FU, in eliciting an effective anti-cancer immunity in mouse hepatoma and colon cancer model systems. The constructed Ad-mFlt3L efficiently infected hepatoma and colon cancer cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCs, NK cells and lymphocytes in local tumor tissues. Administration of Ad-mFlt3L can protect bone marrow injury caused by 5-Fu and stimulates proliferation and maturation of lymphocytes, APCs and NKs. Intratumoral injection of Ad-mFlt3L followed by an intraperitoneal administration of 5-Fu significantly inhibited tumor growth and cured established tumors. Adenovirus mediated Flt3L gene therapy synergies with chemotherapeutic drug, 5-Fu, in elicitation of long-lasting antitumor immunity. The tumor specific immunity can be adoptively transferred into naïve animals successfully by transfusion of CD3+CD8+ T cells from the treated mice. The data suggests that adenovirus mediated Flt3L gene therapy in combination with 5-Fu chemotherapy may open a new avenue for development of anti-cancer chemogenetherapy.