Turning cells into tumor fighters
A gene therapy breakthrough can alter blood cells to turn the immune system into a cancer-fighting machine, reports say.
By TIMES WIRES
Published 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 another 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 in the journal Science. "We're giving living cells which continue to grow and function in the body."
"The important thing is this approach worked," said Dr. Margaret Kemeny, director of the Queens Cancer Center of the Queens Hospital in New York. "Can they make this approach work more often? That is the question."
Melanoma accounts for only 4 percent of skin cancer cases, but it is the most lethal type. More than 62,000 patients will be diagnosed with melanoma this year, and 7,910 people will die from it, according to estimates from the American Cancer Society.
Doctors can't predict how the therapy's first two successful patients will fare long term. Melanoma is notorious for returning years after patients think they have 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.
Origer said his frightening struggle with melanoma began in 1999, when his wife noticed a small, dark mole between his shoulder blades.
After the mole was removed, a biopsy showed it contained melanoma cells. Despite repeated operations and chemotherapy treatments, the cancer continued to spread, he said.
"It's an emotional roller coaster," he said. "You fight it and you feel you've done all you can do and sometimes you get your hopes up and think you've finally defeated it. And then it shows you who's boss."
Origer said doctors finally told him they could not stop the cancer's spread.
"They told me there are some treatments that would buy me a year, but that's all," he said.
He said he and his wife "went to the Internet" in search of clinical trials and learned of the NCI research.
After he was accepted to participate in Rosenberg's research, blood was drawn from his arm and the white cells were separated out.
Rosenberg said some melanoma patients produce white cells that are capable of recognizing telltale "knobs" on the cancer cells.
When these cells encounter a melanoma cell, they "clomp onto (the knob) and inject molecules called perforins that cause the cell to burst open," he said.
However, most melanoma victims and all the victims of other forms of cancer do not produce white cells that can recognize cancer cells, Rosenberg said.
Cancer specialists praised the work, but warned that years of additional research are needed.
"Clearly this is a first step," said 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 said. "It certainly is a proof of concept that this approach will work."
In the Tampa Bay area, a top researcher at H. Lee Moffitt Cancer Center & Research Institute said he's already talking with Rosenberg about studying the technique in patients here.
Jim Mule, Moffitt's associate center director for translational research, said he envisions setting up a consortium of three or four centers around the United States.
"What needs to be done next is to get this promising treatment to other centers, including our own," he said. "To enter many more melanoma patients in trials outside the NCI, to show this approach and this technique are transportable."
In St. Petersburg, Dr. James M. Spencer, a clinical dermatology professor at Mount Sinai School of Medicine, called the news "wonderful."
"Melanoma's a good one to study (with gene therapy) because we don't have any good treatments for metastatic melanoma," said Spencer, who practices at St. Anthony's Carillon Outpatient Center.
Using gene therapy to boost the body's immune system is intriguing, Spencer said, because other attempts to use the immune system with melanoma, by using a vaccine, haven't been successful.
"Melanoma is sneaky," Spencer said. "It evades the immune system by shuffling the (cell) surface proteins. ... There are proteins on the surface that the immune system can recognize, but by the time you get the vaccine, it's no good anymore."
Also, 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 said.
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 said, calling the study "one of the first documented, effective cases of cancer gene therapy working."