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Scientists turn immune cells into tumor fighters to treat melanoma

Friday, September 1, 2006

WASHINGTON -- Mark Origer entered the last-ditch experiment hoping to beat back his melanoma for a few months, long enough to walk his daughter down the aisle. He got far luckier: Almost two years later, his body shows no signs of the aggressive skin cancer.

Government scientists rescued Origer and one other man with advanced melanoma by genetically altering their own white blood cells to turn them into tumor fighters.

The treatment didn't help 15 other melanoma victims. So scientists are trying to strengthen it to work better.

Still, the National Cancer Institute called its experiment, unveiled Thursday, the first real success in the long quest for gene therapy for cancer -- because it fought the disease's worst stage, when it had spread through the body, not just single tumors.

And it did so in a way far different than today's standard options, by harnessing patients' immune systems to continually search out and kill tumors.

"It's not like chemotherapy or radiation, where as soon as you're done, you're done," said Dr. Steven Rosenberg, the NCI's surgery chief who led the research published Thursday by the journal Science. "We're giving living cells which continue to grow and function in the body."

Doctors can't predict how the therapy's first two successful patients will fare long term. Melanoma, which kills almost 8,000 Americans annually, is notorious for returning years after patients think they've subdued it.

"I'm cured for now," is how a grateful Origer, 53, of Watertown, Wis., puts it.

He recalls his doctors' wide grins when, just a month after his December 2004 treatment, his tumors started to shrink. By his daughter's wedding last fall, just one small cancerous spot remained, on his liver. Surgeons later cut it out. A checkup from NCI doctors this week confirmed that Origer is still cancer-free.

"I know how fortunate I am to have gone through this and responded to this. Not everybody's that lucky," he said.

Cancer specialists praised the work, but warned that years of additional research are needed.

"Clearly this is a first step," cautioned Dr. Len Lichtenfeld of the American Cancer Society. "We have to be very cautious about not raising hopes too much."

But "it is exciting," he added. "It certainly is a proof of concept that this approach will work."

More importantly, the gene therapy can be customized to create cells that should attack more common cancers, said Dr. Patrick Hwu, melanoma chairman at the University of Texas M.D. Anderson Cancer Center, who once worked with the NCI team.

In a few months, NCI hopes to begin studying the approach in small numbers of patients with advanced breast, colon and other cancers.

White blood cells called T-lymphocytes hunt down germs and other foreign tissue. But cancerous cells look a lot like healthy cells, making it hard for those T-cells to spot a problem.

By 2002, Rosenberg had made a breakthrough. He found small numbers of cancer-fighting T-cells inside some patients with advanced melanoma. He literally pulled those cells out of their blood, and grew billions more of them in laboratory dishes, enough to have a chance at overwhelming a tumor when they're pumped back into patients. About half significantly improve after this so-called "cell-transfer therapy."

But few melanoma patients make enough cancer-fighting T-cells naturally to spot in their bloodstream, and T-cells that attack other cancers are virtually impossible to find. So Rosenberg and colleagues set out to create those tumor fighters from scratch.

The scientists took normal lymphocytes -- ones that don't recognize cancer -- out of patients with advanced melanoma who had exhausted their treatment options. They infected those cells with a virus carrying genes that create T-cell receptors, essentially homing devices for, in this case, melanoma. (Different genes create receptors for other cancers.)

"We can take a normal cell from you or me or any patient and ... convert that cell into a cell that recognizes the cancer," Rosenberg explained.

Here's the key: When scientists infused the newly armed cells into 17 patients, only Origer and his fellow survivor maintained super-high levels for more than a year -- and only their tumors gradually faded. In most of the other patients, only low levels of the tumor-fighting cells persisted for a few months.

No patients suffered serious side effects, although they required a few weeks of chemotherapy to suppress their natural immune system and make room for the extra T-cells.

Why did those cells flourish in only two people?

"That's the critical question," said M.D. Anderson's Hwu.

Picking the right lymphocyte to genetically alter isn't easy -- there are many different kinds -- or perhaps more precise T-cell receptors were needed for the cells to better take root and do the job, he suggested.

But "these are all solvable issues," Hwu stressed, calling the study "one of the first documented, effective cases of cancer gene therapy working."


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