March 04, 2013
Cancer vaccine ingredient subverts immune attack, diverts it from tumors
BY Scott Merville
For years, scientists have crafted vaccines designed to treat cancer, rather than to prevent it, by priming the immune system to track down and kill tumors.
They identify antigens - distinctive targets - on tumors, combine them with substances (adjuvants) to enhance immune response, and then inject the vaccine to treat a given cancer.
A frustrating pattern emerged, says Willem Overwijk, Ph.D. associate professor in MD Anderson's Department of Melanoma Medical Oncology. In both mouse experiments and human clinical trials, the vaccines created abundant T cells specialized to find the antigen and destroy cells that have it.
These T cells were easily observed in the bloodstream, yet there was little or no effect on tumors in the vast majority of cases.
Overwijk and colleagues decided to focus their attention on potential problems in the vaccine itself. What they found, reported this week in Nature Medicine, could profoundly alter vaccine design and effectiveness.
"We discovered that only a few T cells actually get to the tumor, while many more are stuck or double back to the vaccination site," Overwijk says. [youtube id="VnHM6oqs_4o" align="center" mode="normal"] Mineral oil focuses attack at vaccination site The culprit, the team found, is a mineral oil commonly used as an adjuvant in therapeutic cancer vaccines. The substance, incomplete Freund's adjuvant (IFA), does not break down quickly in the body.
"IFA sticks around the vaccination site for up to three months, along with the antigen designed to trigger immunity against the tumor," Overwijk says. "T cells keep attacking and secreting chemokines to call for reinforcements. But it's an un-killable target; T cells can't kill mineral oil."
T cells pile up at the injection site and die. "The vaccination site increasingly resembles a viral infection, with lots of damaged normal tissue and antigens," Overwijk says.
Substituting a saline solution for IFA reversed T cell traffic patterns, with more accumulating at the tumor and a small amount congregating at the injection site.
Saline-based vaccine puts 30 times more T cells on tumor Cell fluorescence analysis of melanoma tumors in mice showed a 30-fold increase in T cells at the tumor site for those receiving saline-based vaccine compared with those who got an IFA-based vaccine.
A separate experiment using flow cytometry confirmed the accumulation of T cells in the tumor and minimal presence at the injection site in those injected with saline-based vaccine.
Overwijk and colleagues noted 98 federally approved U.S. clinical trials of IFA-based vaccines against a variety of cancers almost all failed. Another 37 trials are open, enrolling patients. The U.S. Food and Drug Administration has approved one therapeutic vaccine, for treatment of prostate cancer.
A clinical trial of with the saline-based vaccines is expected to open later this year led by Craig Singluff Jr., M.D., professor of surgery at the University of Virginia Medical School and Patrick Hwu, M.D., chair of MD Anderson's Department of Melanoma Medical Oncology.
For additional information Full MD Anderson news release Nature Medicine paper