Removing Obstacles To Cancer Vaccine
Researchers at Duke University Medical Center have removed one of the major obstacles that has prevented cancer vaccines from realizing their long-promised potential.
Previous vaccines have failed to generate a strong enough immune response to attack and subdue the tumor, noted the scientists. But the Duke team dramatically boosted immune responses in patients by removing "regulatory T cells" (T-regs) from the bloodstream prior to vaccination. T-regs are suppressor cells in the immune system that inhibit "fighter" T-cells from waging a full-fledged attack on cancer.
Patients who underwent T-reg depletion before receiving a kidney cancer vaccine produced up to a 1,000-fold expansion of fighter T-cells, the study showed. In comparison, patients who received only the vaccine had an immune response 50 times higher than normal.
The Duke team said their findings could have broad implications for all types of therapies aimed at stimulating immune response, not just cancer vaccines.
Results of the study, funded by the NIH, are published in the Dec. 1, 2005, issue of the Journal of Clinical Investigations.
"Ours is the first clinical trial to prove the concept that depleting T-reg cells from the peripheral blood of patients more rapidly and forcefully induces an immune response," said Duke immunologist Johannes Vieweg, M.D., Associate Professor of Urology. "The concept has been tested in mice but has proved to be quite challenging to accomplish in humans, because quantifying and isolating T-regulatory cells is a vastly complex process in humans."
Only three to five percent of human T-cells that co-express the CD4 and CD25 proteins are regulatory, whereas the percentage of such suppressor cells is much higher in mice, he said.
T-regs are the peace-makers of the immune system, reigning in the "fighter" T cells and preventing them from indiscriminately waging war against perceived enemies inside the body. Yet cancer actually boosts production of T-regs as a means of circumventing the immune system's attacks.
The current study is the first to utilize an effective strategy for identifying and isolating T-regs in humans and depleting them from the blood prior to vaccination, said Vieweg. His team identified T-regs in renal cancer patients by measuring expression of a unique protein, Fox P3, which resides inside the cell's nucleus. But this protein is difficult to target with drugs.
So Vieweg's team used an approved cancer drug to attack only those immune cells which over-expressed another marker on the T-reg cell surface called CD25. While all activated T-cells express this protein, T-regs express the highest levels and are thus the target of the drug, called Ontak. The drug is FDA approved to treat cutaneous T cell lymphoma.
Ontak binds to T-regs and is drawn inside the cell, where it attacks the cell's machinery and kills it. In the current study, T-reg depletion occurred rapidly, within several days of being administered to patients, found the scientists.
They administered vaccines to patients with metastatic renal carcinoma four days later. After three vaccinations, the patients demonstrated significantly higher numbers of fighter T-cells that expressed tumor-specific "antigens" - proteins on the surface of cancer cells that trigger recognition and attack by the immune system.
The vaccine alone generated a 50- to 100-hundred fold expansion of fighter T cells, whereas vaccine preceded by T-reg depletion caused up to 1,000-fold expansion of fighter T-cells after 3 vaccinations, the study showed.
Indeed, the latest generation of anti-cancer vaccines is aimed at more robustly alerting the immune system to the enemy at hand and revving its war machinery against the cancer. Cancer is skilled at masking itself from immune recognition, so breaking the immune system's "tolerance" to cancer is essential to an effective vaccine, Vieweg said.
Vieweg's team has partially succeeded in overcoming immune tolerance by creating vaccines that prime the immune system in advance to recognize foreign antigens and immediately present them to fighter T cells.
In this process, the researchers extract specialized immune "dendritic cells" from the patient's bloodstream and mix them together with tumor antigens to create the vaccine. Dendritic cells are the sentries of the immune system that recognize and announce foreign antigens to fighter T cells. By exposing the dendritic cells to antigens prior to vaccination, the dendritic cells are primed to present the antigens immediately after the vaccine is given, said Vieweg.
In recent studies testing a prostate cancer vaccine, dendritic cell vaccines robustly boosted a patient's immune response and reduced the number of tumor cells, said Vieweg. Results of that study were published in the March 15, 2005, issue of the Journal of Immunology.
"The current study is the evolution of a series of five clinical trials testing various cancer vaccines," said Vieweg.
"Each vaccine builds on the strengths of the previous one and incorporates new strategies designed to enhance immune response and remove the barriers that cancer poses to our therapies," said Vieweg.
Duke scientists who contributed to the study include Jens Dannull, Ph.D., David Rizzieri, M.D., Benjamin K. Yang, Doris Coleman, Donna Yancey, Aijing Zhang, Phillip Dahm, M.D., Eli Gilboa, Ph.D., .