Repetitive injections of a synthetic peptide vaccine in combination with a strong adjuvant prevented spontaneous tumors and caused established tumors to regress in a mouse model of HER2/neu breast cancer
LOS ANGELESRepetitive injections of a synthetic peptide vaccine in combination with a strong adjuvant prevented spontaneous tumors and caused established tumors to regress in a mouse model of HER2/neu breast cancer, Pilar Nava-Parada, MD, PhD, said at the 2007 American Association for Cancer Research annual meeting (abstract 4906).
Dr. Nava-Parada was working on her research at Louisiana State University in New Orleans, as part of the Louisiana Cancer Consortium Project, but was sidetracked by Hurricane Katrina. She resumed her work at the Mayo Clinic and with the help of an AACR Saving the Science Relocation Grant, re-established her colony of mice in approximately 16 weeks. Dr. Nava-Parada is currently a postdoctoral fellow at Johns Hopkins University School of Medicine. Senior author Esteban Celis, MD, PhD, is now at H. Lee Moffitt Cancer Center.
The transgenic mouse model used was the female BALB-neuT mouse that carries the activated rat HER2/neu oncogene. This model develops atypical mammary hyperplasia at 10 to 13 weeks, mammary carcinoma at 15 weeks, and palpable and visible tumors at 15 to 25 weeks. Animals were vaccinated with a synthetic rHER2/neu peptide vaccine (p66), in combination with the toll-like receptor stimulant CpG. This agonist adjuvant mimics the way an invading pathogen would induce an immune response in humans; thus, they hypothesized that it would improve responses in the model. In some mice, to enhance the anti-tumor effect, they also used anti-CD25 antibodies, which reduce the production of T regulatory cells that can interfere with vaccine efficacy.
Multiple vaccine strategies were evaluated. Some animals received the vaccine as five daily injections, some received only a single vaccination, and some received boosters. Some animals were immunized prophylactically, with tumor cells injected 7 days after the five daily vaccinations. Others were vaccinated therapeutically, with the tumor cell challenge first, followed by daily vaccinations after tumors developed. These vaccination strategies were also studied in an animal model that spontaneously develops breast tumors, as happens in breast cancer patients.
In general, the vaccine not only produced a cytotoxic T lymphocyte (CTL), ie, CD8 peptide, response but also a strong antitumor response, she said. In 100% of animals, the vaccine induced CD8 T-cell responses and anti-tumor immunity, and either slowed or halted breast cancer progression. In more than one case, the vaccine worked for as long as 39 weeks. "CTL responses and anti-tumor effects can be obtained after the second boost or by a single vaccination when an agonist adjuvant is combined with CD25 antibody therapy. These results suggest that similar strategies should be followed for conducting clinical studies in human patients," Dr. Nava-Parada said.
Mice that were vaccinated with either of the two approaches remained tumor-free or were able to control spontaneous tumor growth and exhibited long-lasting CTL responses against not only the immunizing peptide but also other peptides derived from the rat HER2/neu product, thus indicating epitope spreading. "The body responded by killing everything that expressed HER2/neu in high amounts," she said. Her good results may be due in part to studying a more realistic model than models with established xenografts. "We considered the entire natural history of the tumor in mice with the HER2/neu gene. When the animal had a precancerous lesion, we vaccinated it and followed the appearance of the spontaneous tumor through its life," she said.