Vaccination against an enzyme common to a variety of human tumors might effectively mobilize the body's own immune system to attack and kill cancer cells, scientists from the UCSD School of Medicine and Cancer Center report in the April 4 issue of the Proceedings of the National Academy of Science (PNAS).
Telomerase, an enzyme involved in maintaining normal chromosome length during cell replication and key to the uncontrolled replication of cancerous cells, is considered the first gene to play a direct role in tumor transformation of cells by allowing precancerous cells to become immortal.
A team led by Maurizio Zanetti, M.D., UCSD professor of medicine and member of the UCSD Cancer Center, in collaboration with the Institut Pasteur in Paris, has now successfully used a prototype vaccine in cancer cells in vitro to activate a type of lymphocyte called cytotoxic T-lymphocytes (CTL), or killer cells, to destroy cancer cells using telomerase as a target.
Lymphocytes are white blood cells that patrol the body and, when they encounter foreign cells, launch an attack against the invader. Killer cells target infected or cancerous cells by recognizing and binding to proteins, or antigens, on the cell surface.
"In cancer, the immune system becomes increasingly weakened and ineffective against rapidly proliferating malignant cells," said Zanetti. "We wanted to see if the immune systems of individuals with cancer retained the ability to recognize telomerase, and if we could boost the immune response using telomerase in a prototype vaccine to expand CTL activity against cancer."
Vaccines can bolster this reaction by introducing enough of an antigen to provoke an immune response, amplifying production of CTL against specific targets. Zanetti theorized that by immunizing lymphocytes from cancer patients against telomerase, killer cells targeting telomerase would be generated. Because telomerase activity is elevated in cancer cells, telomerase peptides could then serve as a beacon for CTL, which would zero in on the cancer cells and destroy them.
The team tested a prototype vaccine made from CTL-specific pieces of telomerase reverse transcriptase (hTRT) using blood cells from prostate cancer patients and, for comparative purposes, from healthy individuals. They observed that lymphocytes from prostate cancer patients were readily activated into CTL following immunization with the prototype vaccine, attacking and killing the cancer cells.
They also tested the possibility that because telomerase is over-expressed in the vast majority of all human cancers, CTL produced against one type of cancer would recognize and destroy other types of cancer as well. They added CTL produced in the prostate cancer cell samples to other human cancer cells--breast, colon, lung and melanoma--and found that the killer cells targeted the hTRT peptides in these cells as well and destroyed them.
Experiments also were conducted using transgenic mice provided by the Institut Pasteur in Paris. These mice are genetically engineered to mimic the human immune system, expressing a common type of human transplantation antigen. The prototype telomerase vaccine induced a CTL response in these mice, with no apparent negative side effects, demonstrating the potential of this vaccine in a live model.
Because telomerase is essential in the normal process of cell division, Zanetti and his team also looked for negative effects of this vaccine on normal human stem cells, which have a rapid reproduction rate and therefore higher levels of telomerase than normal cells. No adverse activity was detected. They predict that since telomerase levels in normal cells is low, there is little danger that this approach would cause an autoimmune reaction, with the body attacking its own normal cells. However, they acknowledge that this and other potential problems require further study.
These promising results indicate that telomerase should be further studied as the basis of a vaccine against many types of cancer, activating the body's own defense system and serving as a flag to draw CTL to the cancer cells, according to Zanetti. By demonstrating that the hTRT vaccine effectively promotes CTL activity against tumor cells from cancer patients, Zanetti says the potential of developing a universal cancer vaccine is further advanced.
Co-authors with Zanetti are Boris Minev, M.D.; Jason Hipp and Joseph Schmidt, M.D. of UCSD and the UCSD Cancer Center; and Pierre Langlade-Demoyen, M.D. and Huseyin Firat, Ph.D. of the Institute Pasteur in Paris.