Orally Administered DNA Vaccine Delivery by Attenuated Salmonella typhimurium Targeting Fetal Liver Kinase 1 Inhibits Murine Lewis Lung Carcinoma Growth and Metastasis

• Published in: Biological & pharmaceutical bulletin 2010/02/01, Vol.33(2), pp.174-182
• Main Authors: Zuo, Shu Guang, Chen, Yan, Wu, Zhi Ping, Liu, Xin, Liu, Chun, Zhou, Yong Chun, Wu, Cui Ling, Jin, Cong Guo, Gu, Yu Lan, Li, Jia, Chen, Xiao Qun, Li, Yong, Wei, Hui Ping, Li, Li Hua, Wang, Xi Cai
• Format: Article
• Language: English
• Subjects: Administration, Oral; angiogenesis; Animals; Bacterial Vaccines - administration & dosage; Bacterial Vaccines - immunology; Bacterial Vaccines - therapeutic use; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Carcinoma, Lewis Lung - enzymology; Carcinoma, Lewis Lung - pathology; Carcinoma, Lewis Lung - prevention & control; Carcinoma, Lewis Lung - secondary; Cell Line, Tumor; Drug Delivery Systems - methods; Female; fetal liver kinase 1; Gene Transfer Techniques; Lewis lung carcinoma; Mice; Mice, Inbred C57BL; mouse; Salmonella typhimurium; Salmonella typhimurium - immunology; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - immunology; Vaccines, Attenuated - therapeutic use; Vaccines, DNA - administration & dosage; Vaccines, DNA - immunology; Vaccines, DNA - therapeutic use; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - immunology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.33.174

The vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2), also called fetal liver kinase 1 (FLK1) in mice and kinase insert domain receptor (KDR) in humans, is an endothelial cell specific receptor tyrosine kinase that mediates lung cancer angiogenesis. We hypothesized that an active immunotherapy approach targeting FLK1 may inhibit lung cancer growth and metastasis. To test this hypothesis, we evaluated whether immune responses to FLK1 could be elicited in mice by immunization with an orally administered DNA vaccine encoding the extracellular domain (ECD) of FLK1 (pcDNA3.1-FLK1ECD) carried by attenuated Salmonella typhimurium. We found that the vaccine was effective at protective antitumor immunity in Lewis lung carcinoma models in mice by breaking immune tolerance to FLK1 self-antigen. Both FLK1-specific humoral and cellular immune responses against endothelial cells can be induced in mice by immunization with pcDNA3.1-FLK1ECD. Immunization with pcDNA3.1-FLK1ECD resulted in tumor suppression and prolonged survival in mice challenged with Lewis lung carcinomas cells. Experimental pulmonary metastases were strongly inhibited in pcDNA3.1-FLK1ECD immunized mice challenged with Lewis lung carcinoma cells. Thus, we conclude that the plasmid DNA vaccine encoding the extracellular domain of FLK1 could be an important component of FLK1 DNA vaccine to prevent lung carcinoma recurrence and metastasis after surgery.