The Next Big Thing

With a steadily improving understanding of the immune system, researchers are becoming increasingly crafty in building therapeutic cancer vaccines, using tricks of biology to engage the immune system against cancer. Here are a few of the new approaches:

> Keeping the immune system “on.” Cancer vaccines may contain perfect information about the cancer cells a person’s immune system should target, but the immune system still may not respond. There can be many reasons, says Padmanee Sharma, MD, PhD, of M.D. Anderson Cancer Center, but a crucial one involves the inherent regulation of immune cells called T cells. Researchers now understand that when an antigen—such as those included in a cancer vaccine—stimulates T cells, the T cells themselves begin engaging natural brakes.

“It’s as if a few minutes after you turn on the switch, it’s programmed to turn itself off,” Sharma says. This happens, she says, because immune cells left in overdrive would otherwise begin attacking healthy cells. But in delivering a vaccine to fight existing cancer, researchers want to let the immune cells stay in overdrive, at least for a while.

The natural braking mechanism relies on a molecule called CTLA-4, and blocking this signal with an antibody can prevent braking. Anti-CTLA-4 antibodies are currently part of several cancer vaccine clinical trials, one of which is a melanoma trial testing the anti-­CTLA-4 ­antibody ipilimumab (MDX-010) in combination with a vaccine called MDX-1379.

> Delivery by virus. Vaccine researchers—those interested in cancer as well as infectious diseases—take varied approaches to delivery. One of the oldest tricks is to use dead or weak viruses themselves; the ancient Chinese seem to have warded off terrible strains of smallpox by inhaling dried and powdered pox viruses. Weakened live viruses themselves can be injected under the skin, as with a common form of measles vaccine: Viral strains grown in hen’s eggs are weakened, rarely producing disease in people, but still protect people from later infection.

One of the newest delivery mechanisms is in development at the National Cancer Institute, where Jeffrey Schlom, PhD, and others are using genetic engineering to attach antigens that help the body identify and fight cancer cells to a type of virus called poxvirus. Poxviruses are already used to deliver vaccines against some infectious diseases, but researchers using poxviruses to deliver cancer vaccines, however, can “engineer” the viruses with genes for molecules that further stimulate the immune system.

> Antigens in dead yeast. Another new delivery mechanism involves using yeast cells to build antigens, then killing those cells before injection. “They’re basically little sacs of protein,” says James Gulley, MD, PhD, a cancer vaccine expert at the NCI. “This is just baker’s yeast, but you can put in genes.” The yeast cells pump out the proteins they’re directed to make—an antigen specific to cancer cells, for example.

Researchers today are experimenting with instructing yeast cells to pump out carcinoembryonic antigen (CEA) found in many cancers, including colon, rectal, stomach, breast, and lung. Upon injection into a patient, the patient’s dendritic cells “gobble up the proteins, find all this CEA, and then start telling T cells to attack cells overexpressing CEA. It’s a cool technique, it appears quite safe, and it’s easy to do,” Gulley says. A clinical trial of the technique against several types of cancers expressing CEA is currently under way.