Researchers from the Mayo Clinic, University of South Florida, and University of Torino employed substances called toll-like receptor agonists to help a synthetic peptide vaccine raise the immune system response against breast cancer tumors. Simultaneously, they used antibodies to blunt other aspects of the immune system that might interfere with a strong killer T cell response, improving the effectiveness of the vaccine.
In the February 1 issue of Cancer Research, the researchers report that their strategy was effective in preventing spontaneous tumors in transgenic mouse models for breast cancer, even when the vaccine was given when the mice already had early stage cancer.
"The challenge is to get a foreign peptide recognized by the immune system as a threat so it can react and produce anti-tumor immune cells," said Esteban Celis, M.D., Ph.D., professor in the department of interdisciplinary oncology at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida in Tampa. "We've shown that stimulating the immune system using toll-like receptor agonists is very important to alerting it and producing lymphocytes that will have an anti-tumor effect."
According to Celis, the immune system usually doesn't react as strongly to a synthetic peptide in a vaccine as it does against an infectious agent, which is why immune system boosters such as toll-like receptor agonists, which mimic bacterial DNA, help. They also used anti-CD25 antibodies to tie up immune system T regulatory cells, which often serve as brakes that can reduce responses to the vaccine.
The researchers studied both normal mice and transgenic mice carrying an activated HER2/neu oncogene, which has been linked to breast cancer in humans. In order to get a protective immune response, the transgenic mice were repeatedly given vaccine in combination with the toll-like receptor agonist or were given antibodies that blocked their protective T regulatory cells. Celis and his colleagues found that the peptide vaccine administered this way could prevent or slow the growth of injected tumor cells, and showed some benefit against early stage spontaneous breast tumors.
The vaccine was most effective in preventing spontaneous tumors when it was given once at week eight – along with anti-CD25 antibodies -- when most mice have excessive and often precancerous breast tissue growth called hyperplasia. It completely prevented spontaneous tumors in HER2/neu mice up to 35 weeks of age. Even without the antibody, tumors took much longer to develop, and when they did, they grew more slowly.
"This kind of therapy could be applied to women who have a high likelihood of developing cancer -- women with pre-malignant hyperplasia or who have a genetic predisposition or make-up that makes them at high risk," Celis said.
Although the peptide vaccine was effective in preventing spontaneous tumors in the HER2/neu mice, Celis cautions that the mice had to be vaccinated prior to the appearance of measurable tumors and that the animals had to receive repeated immunizations.
"Once tumors appear, only certain mice respond and there is only a delay in tumor growth," he said. "It extends survival but does not cure the mice. We know that the immune response in these mice is much lower than in the animals that are younger, and it's likely that the tumor is making something that is inhibiting the immune response."
Greg Lester | EurekAlert!
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