Good News About a Very Bad Cancer

24 March 2011 2:01 pm

G. Beatty et al., Science, 331 (25 March 2011)

Going away. A pancreatic tumor that had spread to the liver (left) disappeared after this patient received chemotherapy and an antibody that stimulates macrophages (right).

Pancreatic cancer is relentless and typically kills patients within a few months. Now scientists report that a treatment that fires up certain immune cells extends the lives of pancreatic cancer patients by more than 30%. Although the recipients survived for only about an extra 2 months, cancer researchers are enthusiastic about the results.

The statistics on pancreatic cancer are dismal. Only about 5% of patients with pancreatic ductal adenocarcinoma (PDA), the most common form of the disease, are alive 5 years after diagnosis. And the odds of beating pancreatic cancer haven't improved much in the past 35 years, notes surgeon and cancer researcher Jason Fleming of MD Anderson Cancer Center in Houston, Texas. "We are really at square one with survival," he says.

One of pancreatic cancer's dirty tricks involves co-opting white blood cells called leukocytes. Instead of attacking, these turncoats infiltrate the cancer and "essentially wall it off from the antitumor effects of the immune system," says tumor immunologist Robert Vonderheide of the University of Pennsylvania's Abramson Cancer Center. Vonderheide and colleagues wondered whether they could turn the immune system against the cancer by triggering CD40, a receptor protein carried by several kinds of defensive cells. Activating CD40 is usually necessary for immune cells to take on tumors.

The researchers dosed 21 PDA patients with the standard chemotherapy drug gemcitabine and an antibody that flips on CD40. Computed tomography scans showed that pancreatic tumors dwindled or stabilized in 15 of the subjects. In some of the recipients, the treatment also shrank metastatic tumors, or colonies from the original cancer that had sprouted in other parts of the body. Historically, PDA patients who receive gemcitabine survive about 5.7 months. But as the researchers report online today in Science, patients in the experimental group lived for 7.4 months.

To determine how the treatment curbed tumor growth, the researchers tested genetically engineered mice that develop PDA. The combination of gemcitabine and a rodent version of the CD40-activating antibody—and even the mouse antibody alone—reduced tumors in about 30% of the animals. The researchers expected that activating CD40 would provoke a counterattack by the immune cells known as T cells. But to their surprise, they found that the antibody worked even in mice that lack these cells. Instead, the attackers were macrophages, a more general kind of defensive cell whose jobs include munching bacterial invaders and helping to heal injured tissue. Macrophages were able to squirm through the white blood cell blockade and start killing the tumor cells.

"These are promising results that need to be expanded and tested further in larger studies," says Vonderheide. One question to investigate, he says, is whether other combinations of treatments boost the activator's killing power, such as pairing it with a vaccine that incites T cells to attack the tumor.

Cancer experts are impressed. "It's a great article," says Fleming. "It's definitely a huge step forward," adds cancer biologist Dafna Bar-Sagi of the New York University School of Medicine in New York City. Stretching survival by less than 2 months might not seem like a big deal, but given the poor prognosis for most patients, "these are significant numbers," says molecular biologist Jonathan Brody of Thomas Jefferson University in Philadelphia, Pennsylvania. All three researchers, who were not involved in the study, agree that the results highlight the importance of designing treatments that focus not just on tumor cells but also on the neighboring tissue that helps them survive and grow. "We need to be targeting those cells," Brody says.

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