Scripps Research Institute Group Designs DNA Vaccine That Inhibits Growth Of Cancerous Tumors

"We stimulate the immune system to recognize proliferating blood vessels in the tumor vasculature and to recruit killer T cells to destroy these vessels," explains TSRI Immunology Professor Ralph Reisfeld, Ph.D., who conducted the study with Research Associate Andreas G. Niethammer, M.D., and others. "Deprived of its blood supply, the tumor [eventually dies]."

Niethammer, Reisfeld, and their collaborators describe their successful pre-clinical studies with the vaccine in an article to be published next month in the journal Nature Medicine.

Though not yet tested in humans, their vaccine has the potential to treat many types of cancer, and it may provide a new strategy for the rational design of cancer therapies.

Two Approaches to Treating Cancer

Cancer is not a single disease, but rather over a hundred diseases caused by various sorts of mutations inside various cells in various tissues. Some mutations upregulate genes, increasing the expression of metalloproteinases for instance; others downregulate them, shutting off production of receptor proteins.

After certain mutations occur, a cancer cell grows out of control, dividing over and over and forming a solid tumor. Cancer tumors often damage the tissues where they are located and some can metastasize and migrate through the bloodstream--the malignant carcinoma that claims so many lives every year.

In recent years, some novel approaches to treating cancer have generated interest in scientific circles and society at large.

One of these approaches to is to try to block the process of angiogenesis, the formation of new blood vessels that bring necessary nutrients and oxygen to the hungry tumor cells. Block angiogenesis, the thinking goes, and you can starve a tumor--like drying out a lake by diverting all its tributaries.

The second approach involves attacking the tumor cells directly with a technique known as active immunotherapy. Active immunotherapy involves giving the immune system a push to start killing cancer cells by presenting the so-called killer T cells with tumor-specific antigen. Antigens are markers--proteins on the surface of a cancer cell, for instance--that are used by the immune system to distinguish one cell from another.

Once a killer T cell is presented with the specific antigen, it is stimulated to expand and selectively attack cells that display that antigen. Since cancer cells are originally "self" cells, the trick is to find some antigen that they display, but which normal cells in the body do not. Fortunately, the mutations that cause cancer often cause such antigens to appear on the surface of cancer cells. Sometimes, these antigens are overexpressed on cancer cells, decorating them much more than normal cells, and sometimes the antigens are expressed only on cancer cells. But in any case, when the immune system is stimulated to specifically attack cells with those antigens, the cancer cells can no longer hide behind their "self" facade.

The drawback to immunotherapy is that tumor cells are often very different from one another, confounding attempts to find a single antigen to broadly attack various cancer tumors. Compounding this problem is that even the original tumor can acquire emergent resistance by mutating--as cancer cells often do--and downregulate the target antigens, becoming invisible to the passing killer T cells.

Similarly, anti-angiogenic approaches are complicated by the fact that there are many ways through which a tumor cell can start angiogenesis. Blocking one may simply cause the tumor cells to use another.

But by combining the two approaches, the TSRI team seems to have solved both problems.

Anti-Angiogenic DNA Vaccines--A New Approach

The solution that Niethammer and Reisfeld employed was to target not the tumor cells themselves but the endothelial cells that proliferate to form new blood vessels. Unlike the tumor cells, which readily mutate to resist treatment, the endothelial cells are not prone to mutations and therefore represent a more stationary target.

And targeting the endothelial cells proved effective because these cells are absolutely necessary for tumor growth, since they provide the blood that the tumor cells need to grow.

The DNA vaccine uses an antigen "marker" known as vascular-endothelial growth factor receptor-2 that is upregulated on endothelial cells--particularly those that are undergoing angiogenesis due to nearby cancer tumor growth.

This antigen DNA is inserted into a "targeting vector," the replication-deficient Samonella typhimurium bacteria, which direct the DNA to lymph nodes in the gut--the so-called Peyer's patches. Once there, the bacteria die and release the bits of DNA, which are taken up by professional antigen-presenting dendritic cells and macrophages. Within these cells, the DNA is translated into protein and then presented to T cells.

Once the T cells see the growth factor receptor, they are activated and will circulate through the bloodstream targeting potential tumor-supporting angiogenic endothelial cells that display it.

"We hope that these studies established a proof of concept that may eventually contribute to the development of novel cancer therapies," says Niethammer.

The article, "A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth" was authored by Andreas G. Niethammer, Rong Xiang, Jurgen C. Becker, Harald Wodrich, Ursula Pertl, Gabriele Karsten, Brian P. Eliceiri, and Ralph A. Reisfeld and appears in the November 4, 2002 online edition of the journal Nature Medicine. The article will appear in print in the December 2002 edition of the same journal.

This work was supported by the National Institutes of Health, the American Heart Association, the Tobacco-Related Disease Research Program Grant, the Department of Defense, EMD Lexigen Research Center, and by fellowships through Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft.