Novel DNA vaccines for the treatment of lung cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The overall objective of this proposal is the construction and optimization of DNA-based vaccines for the immunotherapy and prevention of recurrence of lung adenocarcinoma. The use of DNA vaccines differs from traditional (i.e., attenuated viruses, such as smallpox) vaccines, since the subject is not injected with the antigen, but with DNA encoding the (protein) antigen. This grant is a continuation of TRDRP funding from 2000-2003. Our innovative strategy uses an oral ingestion of attenuated Salmonella as a carrier, which delivers the DNA plasmid directly into immune regions (Peyer’s patches) in the small intestine. Thus, the tumor cells do not need to be directly targeted. We have modified and expanded our strategy in this project to include the tumor vascular supply (angiogenesis) and supporting stroma as targets for therapy. This approach focuses on stimulating T cell-mediated killing of key proteins in the proliferating endothelial cells in the tumor microvasculature and stromal fibroblasts, which is expected to result in the eradication of metastatic tumor cells. 
 
 
 
 
 
 
 
 We plan to expand our vaccine strategy by combining tumor-targeted CEA-based DNA vaccine in combination with a second DNA vaccine targeting the vascular endothelial growth factor receptor-2 (FLK-1). Thus, we can develop T cell immunity simultaneously to both tumor cells and the process by which tumor associated endothelial cells from a vascular network. Another complementary approach will involve the construction and critical evaluation of a novel DNA vaccine directed against another receptor tyrosine kinase, Tie-2, which is present in excess amounts on proliferating endothelial cells. Tie-2 binds the angiopoietin 1 and 2 ligands expressed by tumor cells. This provides another level of regulation of tumor angiogenesis, since blocking the activation of the Tie-2 receptor with a DNA vaccine may leave microvessels devoid of associated mural cells, such as pericytes and smooth muscle cells. We hope that targeting Tie-2 will block new blood vessel “sprouts.” In summary, the combination of these two DNA vaccines could be highly effective in suppressing tumor angiogenesis. Finally, we plan to target the supporting tumor stroma, which are mainly fibroblasts that facilitate tumor spread. Thus, a DNA vaccine will be constructed against fibroblast activating protein (FAP), which is selectively expressed only on tumor stromal fibroblasts in human and mouse. We will determine whether this approach causes disarray in the tumor stroma and interfere with such invasive events as the recruitment of tumor stroma and metastasis of tumor cells. 
 
 
 
 
 
 
 
 It is anticipated that achievement of this project’s overall objectives, focusing on the eradication of tumor cells by combining their T-cell mediated killing with suppression of angiogenesis and disarray of the tumor stroma, will lead to efficacious new biotherapies for lung cancer that can be translated to clinical applications.