Two studies presented at the Era of Hope Department of Defense Breast Cancer Research Program meeting exemplify different but equally promising approaches to the development of cancer vaccines. Both approaches capitalize on recent advances in the understanding of the bodys natural disease-fighting mechanisms.
Researchers from the University of Washington, Seattle, developed an experimental cancer vaccine that for the first time generated an immune response against a protein overexpressed in some patients with breast and other cancers by stimulating a response to helper T-cells. Previous vaccine studies have concentrated on stimulating killer T-cells.
This is one of the first trials to show that its possible to generate an immune response to a cancer protein by immunizing patients with fragments of the protein, said Mary L. Disis, MD, associate professor of medicine. It is also the first step toward the long-term goal of developing an affordable and hopefully practical vaccine to prevent cancer recurrence.
The vaccine is made from fragments of HER2/neu. Dr. Disis and her colleagues chose to test HER2/neu as a vaccine after preliminary studies found that some patients had preexisting low levels of immunity to the protein. They hypothesized that a vaccine that boosted this preexisting immunity might induce an antitumor effect.
Production of Helper T-Cells Stimulated
The study, designed to evaluate the vaccines safety and ability to generate an immune response, included 64 patientsall of whom had completed treatment for stage III or IV breast, ovarian, and lung cancer and showed either no evidence of disease or were stable on hormonal therapy. The course of 6-monthly vaccinations was completed by 38 patients. The rest did not complete the study due to disease progression, which required a return to standard treatment.
Of patients who received all six vaccinations, 90% developed an immune response to the protein fragments, and 75% developed an immune response to the protein itself. The vaccine stimulated the production of helper T-cells and was totally nontoxic, said Dr. Disis.
After the course of vaccinations was completed, the researchers continued to monitor a subset of patientswho volunteered for long-term follow-upto see how long their immunity to HER2/neu persisted. Immune responses occurred in some patients who had not shown a response after receiving all six vaccinations; others experienced an increased immune response during the long-term follow-up period. Four patients retained immunity for 2 years or longer after they were vaccinated.
Immune System Remembers
These follow-up data suggest that the immune system may be able to remember and respond to the protein long after vaccination has taken placethe hallmark of a successful vaccine, said Dr. Disis. However, she acknowledged that it will take a larger and longer clinical study to determine whether this vaccine can indeed create long-term immunologic memory and stop cancer from recurring.
The eventual goal of Dr. Disis and her colleagues is to develop a vaccine that could be used routinely to prevent cancer recurrence. In the process, the researchers are currently testing other formulations of the vaccine, using different adjuvants agents, to see which one generates the most effective immune response against the HER2/neu protein. The most promising formulation will be tested for effectiveness in preventing cancer recurrence in patients with stage III breast cancer who are at high risk for relapse.
Novel Delivery of Dendritic Cells
In data presented at the meeting by another research group, significant regression of breast tumors occurred in mice treated with an experimental cancer vaccine. For the first time, researchers injected dendritic cells directly into breast tumors.
The next step is to find the best way of translating these findings into a human clinical trial, said Christopher J. Kirk, phd, a research fellow in the Tumor Immunology Program, University of Michigan Medical Center, Ann Arbor. If this strategy proves effective in humans, the ultimate hope is that immunotherapy with dendritic cells could be used in conjunction with chemotherapy, potentially lowering the chemotherapy doses and thereby reducing side effects while improving efficacy.
In this study, the researchers gave four intratumoral injections of dendritic cells to 25 mice. In 5 of the 25 treated mice, tumors regressed completely for more than 3 months, and new tumors grafted into the same animals did not grow. In the remaining mice, tumor growth was reduced by two-thirds, compared with control mice.
The researchers then gave two injections of dendritic cells combined with tumor necrosis factor (TNF)-alpha directly into breast tumors in another 10 mice. This time, tumors were eliminated in half of the treated mice, and overall tumor growth was reduced by approximately 80%, compared with control mice.
Preliminary Human Studies
In a preliminary study to test the feasibility of this approach in humans, six patients with advanced breast cancer are receiving intratumoral injections of dendritic cells once a week for 3 weeks. (TNF-alpha cannot be given to humans because it produces severe side effects. The researchers are exploring other potential agents that can safely be given to patients to boost the antitumor effect of dendritic cells by causing tumor apoptosis.)
In other studies of cancer vaccines using dendritic cells, the cells have been injected into patients skin, blood, or lymph nodes. This approach requires performing a biopsy first to remove tumor cells from the patient. Then the tumor cells are killed and fed to the dendritic cells in the laboratory. Intratumoral injection of the dendritic cells makes these preliminary steps unnecessary, said Dr. Kirk.
Using dendritic cells to make a cancer vaccine for humans is a labor-intensive process. The cells must be derived from the patients own white blood cells. The white blood cells are grown in the laboratory with proteins that promote the growth of dendritic cells.