With liver cancer rates rising in the U.S. along with obesity and diabetes rates, an experimental vaccine at Georgia Regents University Cancer Center is proving effective in animals and researchers are hoping to speed it along to human trials.
Dr. Yukai He, a Georgia Research Alliance Distinguished Vaccine Investigator at the cancer center, has a $1.6 million grant from the National Cancer Institute to further refine his vaccine approach against hepatocellular carcinoma, which the American Cancer Society said accounts for 80 percent of liver cancers.
Those kinds of cancers are a particular problem as liver cancer rates have tripled during the past 30 years, he said.
“It’s really dramatic,” He said. “There is no cancer that has increased so dramatically this way.”
While some of it is likely due to increasing rates of Hepatitis C and Hepatitis B infections, rising rates of obesity and diabetes are likely to blame for 60 percent of the increase, he said. It’s not clear exactly how those diseases cause liver cancer but it could be that they induce chronic inflammation and damage in the liver, similar to what the viruses inflict, that cause cell mutations that lead to cancer, He said.
While surgery can remove some smaller tumors, there is nothing else that can be done except taking one drug in late stage cases; yet, cancer returns in about 70 percent of those cases, He said. The five-year survival rate is only 16 percent, according to the cancer society.
“There are a few options over there in the clinic,” He said.
Fortunately, most of those particular liver cancer cells show an antigen called alphafetoprotein not seen in normal liver cells, making it a good target for therapy.
Unfortunately, that protein is present a lot during early development and fades away after birth; however, the immune system is still trained to recognize it as part of the body to avoid attacking, so strategies that try to use the normal alphafetoprotein antigen don’t generate much immune response, he said.
Instead, the GRU team took the protein and did a bit of “antigen engineering” in the vaccine to make it look foreign and get the immune system to attack it, He said. The trick is to make it different enough that the immune system will react, but not different enough that the immune system will still be primed to attack the other alphafetoprotein present in the tumor cells and destroy them.
“You have to coax the immune system a little bit so that it will react, but at the same time it can cross-react with the tumor cell,” He said. The vaccine proved very successful in mouse models by reducing the amount of tumors by 80 to 90 percent.
The work shows that using antigens the immune system would normally recognize as part of the body can be successful, said Dr. David Munn, an immunotherapy researcher at the cancer center who has collaborated with He.
“If the tumor expresses it abnormally, then I think the immune system is able to recognize the difference,” Munn said. “There’s a difference between an antigen that is just sitting there in a normal tissue that’s intact and well-behaved versus a tumor that is disorganized, it’s inflamed, it’s not normal. The immune system can use those context cues to recognize them.”
The trick now is coming up with a better delivery system, He said. The mice were delivered the vaccine antigen by an injection using a lentivirus vehicle, a virus in the same family as HIV, but that probably won’t work for humans, he said. What might work is using the vaccine in immune cells taken from the patient and then putting them back in, or by generating a vaccine using a virus-like particle of the protein that can generate the same response, a technique being used to generate some potential influenza vaccines.
In parallel with the work the team is doing in mice, an intramural grant from the cancer center is allowing the team to do similar work using human blood cells, which should help speed up the work to human clinical trials should it prove successful, which so far it has, He said.
“Because we had such good results in the animal model, we want to see if this can work in humans,” he said. “We want to push a little bit faster.”