Durham, N.C. -- A prostate cancer vaccine that trains a patient's own dendritic cells to attack a protein antigen expressed by tumors can robustly boost a patient's immune system and clinically reduce the level of tumor cells in the body, according to the results of an exploratory phase I/II clinical trial conducted at Duke University Medical Center.
"We have more research ahead of us, but the results of this study are promising," said Johannes Vieweg, M.D., Duke associate professor of urology and immunology and senior investigator in the study. "The most exciting aspect about this vaccine is the antigen, telomerase, which is overexpressed in most human cancers. This vaccine has the potential to become a broader vaccine that also could apply to other cancers."
Antigens are protein fragments produced by invaders such as viruses or bacteria that trigger attack by the immune system. A critical challenge in developing vaccines against cancers is to educate the immune system to recognize tumor proteins as foreign antigens.
The results of the study are published in the March 15, 2005 issue of the Journal of Immunology. The research was funded by the National Institutes of Health
Dendritic cells are white blood cells that activate the immune system by capturing antigens and presenting them to the body's killer cells called T cells. In this case, the antigen is telomerase, an antigen secreted by all cancer tumors. Telomerase is an enzyme that elongates stretches of DNA called telomeres at the ends of chromosomes. Since telomere length shortens as cells age, such telomere extension in tumors essentially renders the cells immortal, and thus capable of proliferating.
"Another plus in using telomerase as the target is that the more aggressive a tumor is, the more telomerase the tumor expresses," said Vieweg. "So our vaccine may actually be more effective with a more aggressive tumor because the target becomes more visible to the immune system."
The vaccine developed in the Duke study is created by isolating dendritic cells from the patient's blood. The dendritic cells are then treated with messenger RNA that represents the genetic blueprint for telomerase. The scientists had previously discovered that dendritic cells treated with such messenger RNA molecules will incorporate them into their protein-making machinery, producing the protein antigen and presenting it to T cells.
Once the dendritic cells have been stimulated with the telomerase RNA, they are then injected back under the patient's skin where they activate the T cells to attack tumor cells.
In the trial, 20 men with metastatic prostate cancer were given either a low-dose or a high-dose of the vaccine at different intervals. Twelve of the men received a low-dose vaccine once for three weeks. Eight men were given a higher dose of the vaccine once for six weeks. Overall, the vaccine was well tolerated in both groups, reported Vieweg and his colleagues. Four subjects had fatigue or flu-like symptoms, and all but two patients had inflammation at the site of the injection that subsided after two to three days.
"Patients responded well to the vaccine because we are using materials from their own body to create a vaccine that is designed just for them," Vieweg said.
In the study, the researchers performed immunological tests to ensure that T cells were functioning, and other tests to determine whether number of T cell levels rose during treatment. The immune system has a multi-level system of T-cells, and it is most efficient at battling disease when all lines of T cells are activated and trained on the same target. The first line of defense is the CD8 T cells, while the CD4 T cells work as 'helper' and back up.
In previous Duke studies involving dendritic cell vaccines, the CD8 T cells were sufficiently stimulated, but the CD4 response was poor.
In this study, 19 of 20 patients saw an increase of anti-telomerase CD8 cells. In nine of the patients, the dendritic cells were genetically modified to increase the CD4 response, and all nine saw a greater immune response. Vaccination was associated with a reduction of circulating tumor cells and slowed the increase of PSA levels. PSA, or prostate specific antigen, is a protein whose level in the blood signals the activity of prostate cancers.
"The increase and consistency of the telomerase-specific immune response is exciting," said Vieweg. "We've optimized the vaccine and will continue to build upon this success."
Vieweg said the next step is to move into larger phase II trials where the clinical response will be more closely examined. Such trials are expected to begin in early 2006. He said that the vaccine research will also proceed to applications in hematologic malignancies with 2 studies already being initiated.
Co-authors on the paper include Zhen Su, Jens Dannull, Benjamin K. Yang, Philipp Dahm, Doris Cleman, Donna Yancey, Sylvia Sichi, Donna Niedzwiecki, David Boczkowski and Eli Gilboa, all of Duke University Medical Center. Dr. Vieweg is a consultant for Merix Biosciences and Dr. Gilboa is a stockholder in Merix Biosciences.
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