In Cancer Battles, New Drugs Bulk Up Immune System

by Ben Mauk

June 11, 2008

Drugs that “take the brakes off” immune cell production could become a regular feature of cancer therapy, according to promising human trials.

Once a scrappy underdog of cancer treatments, immunotherapy has a champion in James P. Allison, who received the 2008 American Association of Immunologists–Dana Foundation Award in Human Immunology Research on April 6 for his accomplishments in identifying key mechanisms for stimulating the immune system in cancer patients.

“I hope to make a case for moving immunologists into the mainstream [of cancer therapy],” Allison said at the award ceremony and lecture held at the 2008 Experimental Biology convention in San Diego, which this year encompassed AAI’s annual meeting.

Allison’s research focuses on specific molecules that act as the “gas pedals” or “brake pedals” on the immune system’s cell production efforts. The results have led to new treatments that fight tumors by adjusting the presence of those molecules, he said.

Some of the new treatments are effective in patients who have not responded to other treatments.

“It’s quite an interesting story that’s unfolding,” he said in his lecture. Immunotherapy has been “thought of by too many as some sort of alternative medicine.”

Driving our defenses

When a foreign bacteria or virus, called an antigen, enters the body, it triggers the immune system to produce antibodies, a term that describes many types of proteins capable of identifying and destroying invaders.

Antibodies are produced by a variety of white blood cells, which respond to antigens associated with particular microbes, tumor cells, allergies and other immune threats. Allison’s work centers on members of the white blood cell group known as T cells, defined by the particular antigen receptors on their surface.

In 1982, Allison, now a Howard Hughes Medical Institute investigator at the Memorial Sloan-Kettering Cancer Center, discovered the antigen receptor that alerts T cells to the presence of unusual antigens found on tumors and sparks an immune system response.

Ten years later, Allison demonstrated the necessity of a protein called CD28, which excited T cells to create armies of antibodies. Allison refers to the naturally occurring protein as the “gas pedal” that drives T-cell action. But without a “brake pedal,” T cells would fight indefinitely.

“It’s not just a binary light switch,” he said in an interview. “We knew there had to be something else.”

Then, in 1995, his laboratory demonstrated that the molecule CTLA-4 put a brake on T-cell production.

“We were the lone people out there saying [that CTLA-4] was not a positive (excitatory) molecule,” he said. “You can’t tell right away [whether] you took away a negative (inhibitory) factor or added a positive.”

However, once CTLA-4’s inhibitory effects were discovered, Allison’s lab collaborated with Medarex, Inc. and Bristol Myers Squibb to develop a drug, ipilimumab, to suppress CTLA-4’s effects.

“We [had] the notion that if we just used antibiotics to get rid of CTLA-4 we could ‘take the brakes off’ T-cell production,” Allison said in his lecture. “This was a very compelling thing to try. Since we’re messing with the immune system [the treatment] can be used with any kind of cancer,” meaning that the treatment would not be susceptible to the mutations in tumor cells that foil traditional vaccine treatments.

Tag-team therapy

Ipilimumab has been tested on more than 2,000 patients with advanced renal, bladder, ovarian and other cancers, with positive results even in some patients with stage 4 metastatic melanoma (the most serious of skin cancers).

Of patients with melanoma or renal cancers, 15 to 20 percent responded to the immune checkpoint blockade therapy alone; one-quarter of those saw a complete eradication of the tumor threat. Some patients have had a stable remission up to six years after the treatment began.

Furthermore, these studies involved only one therapy. Using mouse studies, Allison's lab has explored combining the drug with chemotherapy, with even better results. Allison thinks drugs such as this one might be used in conjunction with other treatments in the doctor’s office.

“Certainly, use both immunotherapy and chemotherapy. It’s assumed that all chemotherapy beats up the immune system, but some don’t,” he said during the interview.

Allison noted that the drug did carry the risks associated with autoimmunity—that the immune system might become too active and begin to attack healthy cells. He knows the importance of stressing such caveats.

“It’s changing, but cancer immunotherapy has a long history of being checkered,” Allison said.

“Part of it is our fault,” he admitted. “Something new comes up and we hype it.” Then, when the results do not meet expectations, “people go, ‘Eh.’ ”

Redefining vaccines

For their part, pharmaceutical companies are taking it slow. Medarex and Bristol-Myers recently announced that they will not seek the necessary biologics license approval for ipilimumab in 2008, citing an FDA request for additional survival data.

A separate hindering factor is the standard measurement of success for cancer therapies, Allison said. Traditionally, the tumor must disappear without further growth, and no new lesions can appear, for a treatment to be termed a “success.”

“These criteria make no sense whatsoever to use with immunotherapy,” Allison said. “All our mouse trials would have failed with those criteria. The tumors do grow before they disappear. A ‘failure’ becomes a success.”

“What we need to do is look at anything that kills tumor cells as a vaccine,” he said, including drugs that act on the immune system.

From his vantage point at the AAI meeting—at the center of forward-looking immunology research—Allison speculated about how other advances could change the field in the near-future.

He suggested that “new DNA-sequencing [techniques] will advance so fast that we will be able to go into individuals. One person, one vaccine. This is coming. I think the immune system has a chance of sorting out the new proteins made by mutations.”

In the AAI president’s lecture, Olivera Finn spoke of the potential for developing cancer vaccines based on the bacterial infections and viruses that strengthen a child’s developing immune system, and that have been shown to help the body fight tumors later in life.

In short, Allison said, “You're not ever going to cure cancer unless you engage the immune system.”

The AAI-Dana Foundation Award in Human Immunology Research is presented every year in recognition of an individual's “significant and sustained achievement in immunology research pertinent to human disease pathogenesis, prevention and therapy.”