Yvonne J. Paterson, PhD

2008-2010 BCRF-AACR Project:
"Anti-Angiogenesis Immunotherapy for Treatment of Metastatic Breast Cancer"

The ideal therapy for breast cancer would require limited administrations, be specific, non-toxic, inexpensive and would provide life-long protection from multiple cancer types. Immunotherapy is a type of therapy that instructs the immune system to specifically attack only cancer cells. This is done by engineering non-pathogenic bacteria to over-express a tumor protein such that when this bacterium induces an anti-bacterial immune response it will also generate a parallel, and just as potent, anti-tumor response. Bacteria are used to carry and disguise our tumor protein as a bacterial protein, this tricks the immune system into thinking that it needs to attack all cells expressing this particular protein, and since only tumor cells in the body express this protein then only cancer cells will be targeted. The immune system is very specific, is not toxic, and will provide life long immunity. Dr. Paterson’s lab is focused on expressing these tumor proteins in the bacterium, Listeria monocytogenes, which is commonly found in dairy products, is innocuous in healthy people but causes disease in immunocompromised individuals, like AIDS patients and pregnant women.

The work supported by the AACR and BCRF grant proposes an idea that goes a step beyond targeting specific tumor proteins—it targets the tumor’s blood supply. This approach makes the therapy applicable to more than just breast cancer. It could be used to treat all sorts of cancers because all tumors need a constant supply of blood to carry nutrients, oxygen, and remove wastes. This therapy targets blood vessels that are newly forming (a process called angiogenesis), so tumors that are growing for the first time, for example, after metastasis, will be most affected by this therapy. Since new blood vessels do not usually form in adults unless during pregnancy or wound healing, then the only source of rapidly dividing vessel cells are growing tumors. Thus targeting angiogenesis using immunotherapy will provide life long immunity against rapidly dividing tumors by attacking their food supply.

In this study Dr. Paterson and colleagues are making Listeria monocytogenes based therapeutics that will target certain proteins involved in angiogenesis to the immune system. They have shown that vectors that express each of two of these proteins, one that destroys specialized cells that maintain the integrity of the vasculature and one that targets a receptor that signals the formation of the cells of which blood vessels are composed, are effective in preventing the metastatic spread of breast cancer in laboratory models of the disease. They are still working on constructing a Listeria strain that will target a third molecule important in angiogenesis. When they have settled on the most effective target molecule, they will test this therapy in combination with existing known therapies to enhance the overall anti-tumor response, in hopes of providing a possible alternative therapy for patients against breast cancer that may also provide additional protection against metastatic spread.

Mid-Year Progress Report:
In this study Dr. Paterson and colleagues are making Listeria monocytogenes based therapeutics that will target certain proteins involved in angiogenesis to the immune system. They have shown that vectors that express each of two of these proteins, one that destroys specialized cells that maintain the integrity of the vasculature and one that targets a receptor that signals the formation of the cells of which blood vessels are composed are effective in preventing the metastatic spread of breast cancer in models of the disease. They are still working on constructing a Listeria strain that will target a third molecule important in angiogenesis. When they have settled on the most effective target molecule, they will test this therapy in combination with existing known therapies to enhance the overall anti-tumor response. This will provide a possible alternative therapy for patients against breast cancer that may also provide additional protection against metastatic spread.

Bio:
Yvonne Paterson is a Professor in the Department of Microbiology and Associate Dean for Postdoctoral Research Training at the University of Pennsylvania. Dr. Paterson received her PhD degree in 1979 from the University of Melbourne, Australia and then went on to do her postdoctoral work at Cornell University. She currently holds the position of Director for multiple programs including the IRACDA Post-Doctoral Training Program for Teaching and Research, The Pre-Doctoral Emphasis in Tumor Immunology Training Program from the CRI, and the NCI Training Program in the Immunobiology of Normal and Neoplastic Lymphocytes. She has previously served as a member of the AACR Immunology Program Committee and is currently a member of the FASEB publications committee. She was recently elected a Fellow of the ASM and of the AAAS.

Dr. Paterson has published more than 100 peer-reviewed articles. Her research is dedicated to harnessing the immune system to provide cures for, or protection against, neoplastic disease. To this end, her laboratory is using a facultative intracellular bacterium, Listeria monocytogenes, which has the unusual ability to live and grow in the cytoplasm of the cell. Dr. Paterson's laboratory was the first to show that this bacterium could be used to target antigens to the MHC class I pathway for antigen processing with the induction of cytotoxic T cells and she has pioneered the application of this organism in vaccine development over the past 15 years. Cancers to which they are directing their focus include cervical cancer, breast cancer, lung cancer, melanoma and lymphoma.