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Online Extra: Doubling-Up on Cancer Drugs


When treating cancer, oncologists rarely depend on just one drug to destroy marauding tumor cells. Instead, they use what's often called a "cocktail therapy," administering a number of drugs, either together or sequentially, in the hopes that the combinations will somehow make each component more potent. Genentech's (DNA) Avastin, for example, which cuts off the blood supply to tumors, is most effective when combined with other treatments.

Combination therapy may ultimately be the key to success for the emerging field of therapeutic cancer vaccines, designed to prod the body's immune system into attacking tumor cells. None of the 60 or so experimental vaccines currently in human trials have yet to prove unqualified efficacy at shrinking tumors, though there are signs that they can keep patients alive longer. But some scientists say an unusual new drug under development by Medarex (MEDX) and Bristol-Myers Squibb (BMY) may boost the tumor-killing ability of vaccines.

The Medarex drug, which goes by the unwieldy name of ipilimumab, doesn't attack cancer cells. Instead, it releases one of the brakes our bodies apply to the immune system so that disease-fighting drugs can do their job unimpeded. Ipilimumab may have little effect on a tumor on its own, says Alan Houghton, head of the tumor-immunology laboratory at Memorial Sloan-Kettering Cancer Center in New York, just as therapeutic vaccines have had little success in reducing the size of tumors. "Combine these two, and the immunological response goes to 100%," he says.

IMPORTANT INTERACTIONS Ipilimumab is currently in several clinical trials, alone and with other vaccines. The most closely watched is a small combination trial in the Netherlands with GVAX, an experimental prostate-cancer vaccine from Cell Genesys (CEGE). Twelve patients have been treated so far, and in February the companies reported that five of the six patients who got the strongest dose saw their prostate specific antigen (PSA) level, a marker that can indicate the spread of prostate cancer, drop by more than 50%.

For four of those, the decline lasted for more than six months, and one patient experienced a decline for more than 12 months. That's considered a significant length of time for such sick patients. The combination also reduced the tumor size of one patient and reduced deadly bone metastases. GVAX has yet to prove such a strong anti-tumor reaction on its own.

The secret to the Medarex drug lies in a complex set of interactions in the immune system that's still not well understood. The immune system is designed to attack foreign invaders such as viruses and bacteria, sending out a barrage of so-called T-cells to destroy it through inflammation or some other reaction. But T-cells ignore the homegrown cancer cells, assuming that anything that arises inside the body must be benign.

ATTACKING TUMORS In recent years, scientists discovered that a part of the immune system called a dendritic cell, which marshals the T-cells to attack, can also send out a molecule called CTLA-4 that slows or stops those same T-cells. CTLA-4 protects the body from immune overreactions, but it also seems to be activated in the presence of mutant cancer cells—the dendritic cells want to protect those as well.

Ipilimumab is an antibody that blocks CTLA-4, removing the safety brake. It was discovered about seven years ago by James Allison, then at the University of California, Berkeley, and now head of the immunology department at Sloan-Kettering. Allison found that the antibody had the remarkable ability to completely knock out tumors in mice.

But the drug started attracting serious interest from the cancer community in 2003, after Glenn Dranoff at Dana-Farber Cancer Center in Boston gave the drug to patients with late stage melanoma and ovarian cancers, who had already received therapeutic vaccines with little benefit. All five patients given the most potent vaccine showed widespread death of cancer cells, proof that the immune system was on the attack.

PROCESS OF ELIMINATION The problem with drug combinations, however, is that it can be difficult to discover which component is doing what, especially in some clinical trials. Cancer-vaccine skeptics suggest that patients who benefited from a vaccine plus ipilimumab may have done just as well on the Medarex drug alone. "It can be effective in about 15% of melanoma patients, and it also has some reactivity in kidney cancer, but there's no evidence that a vaccine adds anything to it," says Steven Rosenberg of the National Cancer Institute, who has tested patients using ipilimumab.

Medarex and Bristol-Myers, which signed on to co-develop the drug in 2005, hope to settle the question with three large, late-stage trials of the drug, one where it's tested on its own, one where it's combined with chemotherapy, and one with a cancer vaccine. Results will start rolling in later this year. The drug is also being tested with a number of other vaccines in Phase 2 trials. Oncologists hope that, if and when it wins market-approval, they will be able to start experimenting with any number of drug combinations to see what it will contribute.

"We have become increasingly aware of the multiplicity of control points in the immune system," says Dana-Farber's Dranoff. "We have to figure out the relative importance of each of those control points, so we can come up with the optimal treatment. This is a problem that will require careful testing in patients." By Catherine Arnst


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