Novel DNA vaccines for the treatment of lung cancer

Institution:	Scripps Research Institute
Investigator(s):	Ralph Reisfeld, Ph.D.
Award Cycle:	2003 (Cycle 12)	Grant #: 12RT-0002	Award: $783,900
Subject Area:	Cancer
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

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.

Publications

A DNA vaccine encoding murine Tie-2 suppresses effective angiogenesis and induces protection against tumor growth.
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

A DNA minigene vaccine against VEGF receptor 2 (FLK-1) suppresses angiogenesis and successfully inhibits growth of prostate and lung carcinoma in mice
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

A novel strategy to suppress lung tumor growth with a DNA vaccine targeting survivin.
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2003	Vol:	Nbr:	Abs:	Pg:

An oral DNA vaccine against human carcinoembryonic antigen (CDA) prevents growth and dissemination of Lewis lung carcinoma in CEA transgenic mice.
Periodical: Vaccine			Index Medicus:
Authors: Niethammer AG, Primus FJ, Xiang R, Dolman CS, Ruehlmann JM, Gillies SD, Reisfeld RA				ART
Yr: 2001	Vol: 20	Nbr:	Abs:	Pg: 421-429

A DNA vaccine against vascular endothelial growth factor receptor 2 prevents effective angiogenesis and inhibits tumor growth.
Periodical: Nature Medicine			Index Medicus:
Authors: Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Reisfeld RA, et al				ART
Yr: 2002	Vol: 8	Nbr:	Abs:	Pg: 1369-1375

DNA vaccines suppress tumor growth and metastases by the inductiin of anti-angiogenesis,
Periodical: Immunological Reviews			Index Medicus:
Authors: Reisfeld R.A				ART
Yr: 2005	Vol: 199	Nbr:	Abs:	Pg: 181 - 190

DNA Vaccine Targeting Survivin Combines Apoptosis with Suppression of Angiogenesis in Lung tumor eradication,
Periodical: Cancer Research			Index Medicus:
Authors: Xiang, R., Mizutani, N., Luo, Y.,				ART
Yr: 2005	Vol: 65	Nbr: 2	Abs:	Pg: 553 - 561

A DNA vaccine encoding murine Tie-2 suppresses effective angiogenesis and induces protection against tumor growth.
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

A DNA minigene vaccine against VEGF receptor 2 (FLK-1) suppresses angiogenesis and successfully inhibits growth of prostate and lung carcinoma in mice
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2004	Vol:	Nbr:	Abs:	Pg:

A novel strategy to suppress lung tumor growth with a DNA vaccine targeting survivin.
Periodical: American Association for Cancer Research			Index Medicus:
Authors: Reisfeld RA				ABS
Yr: 2003	Vol:	Nbr:	Abs:	Pg:

An oral DNA vaccine against human carcinoembryonic antigen (CDA) prevents growth and dissemination of Lewis lung carcinoma in CEA transgenic mice.
Periodical: Vaccine			Index Medicus:
Authors: Niethammer AG, Primus FJ, Xiang R, Dolman CS, Ruehlmann JM, Gillies SD, Reisfeld RA				ART
Yr: 2001	Vol: 20	Nbr:	Abs:	Pg: 421-429

A DNA vaccine against vascular endothelial growth factor receptor 2 prevents effective angiogenesis and inhibits tumor growth.
Periodical: Nature Medicine			Index Medicus:
Authors: Niethammer AG, Xiang R, Becker JC, Wodrich H, Pertl U, Karsten G, Reisfeld RA, et al				ART
Yr: 2002	Vol: 8	Nbr:	Abs:	Pg: 1369-1375

DNA vaccines suppress tumor growth and metastases by the inductiin of anti-angiogenesis,
Periodical: Immunological Reviews			Index Medicus:
Authors: Reisfeld R.A				ART
Yr: 2005	Vol: 199	Nbr:	Abs:	Pg: 181 - 190

DNA Vaccine Targeting Survivin Combines Apoptosis with Suppression of Angiogenesis in Lung tumor eradication,
Periodical: Cancer Research			Index Medicus:
Authors: Xiang, R., Mizutani, N., Luo, Y.,				ART
Yr: 2005	Vol: 65	Nbr: 2	Abs:	Pg: 553 - 561