New Lymphoma Drug Shows Promise

THURSDAY Aug. 14, 2008 -- Preliminary results from an early trial of a new immunotherapy suggests doctors may soon have another weapon for the treatment of non-Hodgkin lymphoma.

A team of German scientists and clinicians led by Patrick Baeuerle, chief scientific officer at Micromet AG, a Munich-based biopharmaceutical company, demonstrated partial or complete tumor regression in 11 of 38 human patients given low doses of blinatumomab, a protein that tethers tumor-killing T-cells to cancerous B cells.

Each of these 38 patients had already tried a median of three standard therapies for non-Hodgkin lymphoma, and their prospects were grim, Baeuerle said.

"They could have died within months to a year or two," he said. "They were all terminally ill patients."

Four patients, all of whom received at least 30 micrograms per square-meter per day for between four and eight weeks, have been in remission at least six months; the longest has been cancer-free over 13 months.

The research was published in the Aug. 15 issue of Science.

Non-Hodgkin lymphoma (NHL) is not a single disease. Rather, it is an umbrella term for at least 27 distinct immune system cancers, said Dr. Barton Kamen, chief medical officer of the Leukemia & Lymphoma Society. According to National Cancer Institute figures, there will be about 66,120 new cases of NHL in the United States in 2008, and 19,160 deaths.

NHL can involve either B or T immune cells. Blinatumomab targets that group of cancers that are caused by B cells, such as follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia.

The drug is what its authors call a BiTE, a kind of antibody that flags foreign particles and infected cells for immune clearance. Normally, antibodies contain two arms, each of which binds one copy of the same molecule, such as a specific protein on the surface of a bacterium or virus. Blinatumomab, though, is different: one arm binds T-cells, and the other, B cells.

"T-cells are field marshals of the immune system," explained Dr. Thomas Kipps, of the Moores UCSD Cancer Center in La Jolla, Calif. "They direct traffic, recognize when foreign invaders come into the body, and they can induce formation of killer cells to go after the invader."

In this case, the drug induces the T-cells to attack cancerous cells, long a goal of cancer researchers.

"The antibody decorates tumor cells so any passing T-cell touching that cell briefly will adhere to it much longer than normal, and then the whole program of cell killing is kicked off," Baeuerle said.

That approach is different from the one used by most antibody therapeutics, which flag diseased cells but do not necessarily recruit T-cells to kill them, Kipps said.

"I think it's exciting that we have new tools to treat cancer," Kipps said. "Whenever you have specificity to act against the cancer cell and also solicit host systems to combat the cancer, I think that's an advance."

"The promise of this technology is phenomenal," Kamen added.

That's because similar BiTE compounds, designed to target other kinds of cells, can easily be built by replacing the B-cell-targeting arm with one targeting, say, melanoma or breast cancer cells.

Baeuerle said Micromet has already developed and is testing other BiTEs against, for instance, EpCAM, a molecule that decorates a variety of solid tumors such as colon and lung cancers.

One potential drawback of blinatumomab, both Kamen and Kipps said, involves its mechanism of targeting B cells. Rather than homing in on diseased cells in particular, the drug targets all B cells. As a result, it leads to rapid depletion of B-cell pools.

"If I give this to a person with a normal immune system, will I take out all the B cells?" Kamen asked. "Probably, and you have to ask yourself what the significance of that is."

Kamen was impressed with the drug's apparent potency. While rituximab, another antibody therapeutic for NHL, is typically dosed at 375,000 micrograms per square meter per day, the authors of the current study saw effects at levels of 30 micrograms. "That just speaks to the biology and pharmacology here," he said.

As the current trial continues, additional trials, such as a phase 2 study of the drug's effect against acute lymphoblastic leukemia, a particularly aggressive disease, have been initiated, said Baeuerle. Preliminary data are expected at the American Society of Hematology annual meeting in December.

More information

For more on non-Hodgkin lymphoma, please see Non-Hodgkin's lymphoma information at Drugs.com.

Posted: August 2008


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