Initial Clinical Study Shows Safety and Bioactivity of Cancer Vaccine
DURHAM, N.C. -- A new phase I clinical trial of a prostate cancer vaccine developed at Duke University Medical Center has shown that the vaccine made from the patient's own dendritic cells causes no adverse side effects. More importantly, the trials indicate that the vaccine is able to boost the patient's immune system to fight cancer.
The results of this trial in 13 patients are published in the February 2002 issue of the Journal of Clinical Investigations.
"This is the first study that has data on the safety and immunological efficacy of this type of cancer vaccine," said Dr. Johannes Vieweg, an associate professor of urology and assistant professor of immunology at Duke University Medical Center and senior investigator in the study. "And while this work was done in prostate cancer patients, we believe this method may prove to work in most cancers, not just prostate cancer."
Dendritic cells are white blood cells that activate the immune system by capturing antigens — substances that trigger an immune response, such as against a virus, bacteria or tumor — and presenting them to the body's killer cells, called "T cells." The vaccine created in the Duke study introduces genetic information from a prostate cancer patient's own dendritic cells, in the form of RNA from prostate-specific antigen (PSA). This antigen is secreted by the prostate gland and is elevated in some forms of prostate cancer. Once the dendritic cells use the RNA to produce and present the PSA antigen, they are injected back under the patient's skin and activate the T cells to attack tumors.
In the trial, 13 men with metastatic prostate cancer were given three escalating doses of the vaccine. Overall, the vaccine was well tolerated, reported Vieweg and his colleagues. Four subjects had low-grade fevers and flu-like symptoms, and four 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," said Vieweg.
In the study, the researchers performed immunological tests to ensure that T cells were functioning and able to kill tumor cells, in addition to tests to determine whether the T cell levels rose. In all 13 participants, the researchers detected activation of PSA-specific T cell responses, suggesting the vaccine was successful in boosting the immune system and turning T cell attention to the cancer.
Vieweg said that the immunological data, which is sometimes not collected in such trials, is highly important in proving that the cancer vaccine is working in the patient and other influences are not at work.
"Some studies examine only if there is a reduction in tumor growth, but this would only show part of the story," he said. "You wouldn't see the subclinical changes in the body that might indicate that a vaccine is promising. Immunological studies are time-consuming and complex, but extremely important when linking a cause-and-effect relationship between the vaccine and the data we collect. We often might not see a clinical regression of the tumor, but we might see signs that the vaccine is working in the immunological data. It's all about small steps."
The Duke study was not designed to track tumor regression because the small trial was aimed at determining only whether the vaccine was safe and effective in stimulating T cell response. However, the researchers tracked PSA levels in seven of the 13 patients. Six were excluded because they required radiation treatments for preexisting tumors or they took herbal supplements that could impact PSA levels. In the remaining seven, six had a significant decrease in PSA levels and three patients exhibited a decrease in free-circulating tumor cells detected in the blood.
According to Vieweg, the next step is to use fully mature dendritic cells and program them to carry multiple tumor antigens rather than just PSA. Vieweg cautioned that a possible side effect of a more potent vaccine might be that it could overactivate the immune system and cause T cells to attack healthy cells. However, Vieweg said that if such a problem were to occur, it could be adjusted easily by withholding vaccine booster shots, changing the dose or changing the antigen.
The study was supported by grants from the National Institutes of Health, the CaP CURE Foundation, and the National Center for Research Resources.
Other authors of this study include: Axel Heiser, Doris Coleman, Jens Dannull, Donna Yancey, Margaret A. Maurice, Costas D. Lallas, Philipp Dahm, Donna Niedzwiecki and Eli Gilboa, all of Duke University Medical Center.