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Antibody Drug Unleashes Tumor-Killer T Cells

Trial of a two-pronged antibody that attacks late-stage cancer finds it is safe and effective—even at relatively low doses
cancer antibody lymphoma Micromet



© ISTOCKPHOTO/PHOTO168

Scientists have developed a two-pronged protein that grabs immune system cells with one arm and introduces them to cancer cells it has snagged with the other. The result: eradicated tumors—at certain doses.

The technology is only in early human clinical trials, but if it proves effective, this new antibody—a protein employed by the immune system to ferret out foreign invaders—could offer way to stop non-Hodgkin's lymphomas, a type of cancer, in its tracks.

More than 65,000 Americans have been diagnosed with non-Hodgkin's lymphoma thus far in 2008, according to the National Cancer Institute, and nearly 20,000 have died from it. The standard care for this type of cancer is a course of the antibody-based drug Rituxan combined with four chemotherapy agents; the latter compounds often kill normal cells, along with cancerous ones.

Researchers at Bethesda, Md.–based biotechnology company Micromet, Inc., report in this week's Science that in a 38-person trial designed primarily to determine the safety of their drug blinatumomab (which incorporates the protein), 11 showed significant responses to therapy that included a shrinking of cancerous lymph nodes.

Here's how it works: The two-pronged protein is part of a fleet of such antibodies that Micromet calls BiTEs (bispecific T cell engagers), which like to stick to proteins on the surfaces of cancer cells and T cells—the immune system cells that coordinate and attack foreign invaders. Whereas the T cell prong remains the same in each BiTE, Micromet can change out the other end to target specific types of cancer—blinatumomab specifically looks for lymphoma, for example. When the cells are brought together, the T cells are transformed into vicious killers—literally called killer T cells, because they do the dirty work of wiping out the cancer cells

All of the patients in the Micromet trial had advanced stage lymphomas and had been through at least one standard treatment course—most likely involving a harsh chemotherapy that wipes out normal cells in addition to the cancers it's been sent to eradicate. Some of the patients had been through up to 12 treatment regimens without their cancer responding.

In the trial, patients wore port systems where blinatumomab was continuously pumped through their chests and into the bloodstream by pumps on their belts. The patients were split into several groups with some receiving a low daily dosage, as little as 0.01 microgram, up to a high of 0.1 microgram. All of the patients that received the highest dose of blinatumomab responded well to treatment, with one person remaining in remission for more than a year.

Micromet was surprised to see a response at such a low dose, says Patrick Baeuerle, the company’s chief scientific officer and a co-author of the Science paper.

The treatment was not without side effects, though Baeuerle calls them "manageable." Patients reported chills, fever and fatigue—a normal consequence of the immune system activating. In addition, he notes, some volunteers experienced flulike symptoms as well as disorientation, speech impediments and tremors—though all these behaviors diminished a few days after treatment began.

Cassian Yee, an immunologist at the Fred Hutchinson Cancer Research Center in Seattle, said the new antibody is convenient and appears to be effective at low doses. He did caution that because T cells are converted into tumor killers only when it is in the bloodstream, patients may need to continue treatment even after their cancer has gone into remission.

Next, Baeuerle says, the Micromet team will increase the dosage in patients, to figure out the highest dosage of blinatumomab that a person can tolerate. He notes that because the drug is still in early testing, its cost to patients—should it be approved for use—"is a moving target."

He adds that attacking lymphoma is just the beginning. Micromet will soon be testing similar drugs against lung and skin cancers.

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