Cancer-fighting vaccines stimulate immune cells to recognize tumor cells as foreign and destroy them. Physicians believe a vaccine-induced immune response could be used to supplement other cancer therapies or to immunize high-risk people against cancer.
"We've been studying a protein called mammaglobin-A found in 80 percent of breast tumors," says Thalachallour Mohanakumar, Ph.D., the Jacqueline G. and William E. Maritz Professor of Immunology and Oncology in the Department of Surgery and at the Siteman Cancer Center. "The protein is especially interesting for cancer immunotherapy because of its frequent occurrence and because breast tumors express it at high levels."
In articles in the Journal of the National Cancer Institute and Breast Cancer Research and Treatment, the researchers report that they constructed a vaccine consisting of copies of the DNA sequence that makes mammaglobin-A in humans.
The researchers theorized the DNA vaccine would rev up special immune cells called T cells to recognize mammaglobin-A as a foreign molecule when it is displayed on the surface of cells as an antigen (a small protein that the immune system may recognize). The primed T-cells then would proliferate and attack when they met with mammaglobin-A antigens.
"Mammaglobin-A is involved in breast development and secreted in breast milk," Mohanakumar says. "So we had to prove first that we could elicit an immune response to a protein that is in the body normally."
They injected the DNA vaccine under the skin of test mice that had been engineered so that their immune systems would react to the human mammaglobin-A like a human immune system. The researchers loaded specific cells in the mice with mammaglobin-A antigens and found that the vaccine-primed T-cells attacked those loaded cells.
The research team also transferred vaccine-primed T cells into mice with growing tumors that had or didn't have mammaglobin-A antigens. Tumors with mammaglobin-A antigens stopped growing and shrunk in volume, while those without the antigens continued to grow at the usual pace.
"The results demonstrated that the vaccine-primed immune response is specific to mammaglobin-A antigens," Mohanakumar says.
Breast tumors with mammaglobin-A antigens on their surface also may display antigens that come from multiple parts of the mammaglobin-A molecule. Further experiments confirmed the importance of generating T cells that can react to a variety of different mammaglobin-A antigens.
When the research team tested a DNA vaccine containing the DNA code for just one part of the mammaglobin-A molecule, they found T cells reacting to only that antigen, indicating that the method can generate immune cells that target specific parts of the mammaglobin-A protein.
"Now that we've found how effectively an immune response can be generated to mammaglobin-A, we plan to conduct clinical trials in patients who are at very high risk for breast cancer and in patients who have had a relapse after initial treatment," Mohanakumar says. "We want to see if giving patients the DNA vaccine can prevent or eliminate breast cancer or at least slow its growth."
Narayanan K, Jaramillo A, Benshoff ND, Campbell LC, Fleming TP, Dietz, JR, Mohanakumar T. Response of established human breast tumors to vaccination with mammaglobin-A cDNA. Journal of the National Cancer Institute 2004 Sept 15;96(18):1388-1396.
Jaramillo A, Narayanan K, Campbell LG, Benshoff ND, Lybarger L, Hansen TH, Fleming TP, Dietz JR, Mohanakumar T. Recognition of HLA-A2-restricted mammaglobin-A-derived epitopes by CD8 cytotoxic T lymphocytes from breast cancer patients. Breast Cancer Research and Treatment 2004; 88:29-41.
Funding from the Susan G. Komen Breast Cancer Foundation supported this research.
Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. The Siteman Cancer Center is the combined cancer programs of Washington University and Barnes-Jewish Hospital.