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Cross Hairs On Cancer


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Cross Hairs On Cancer

An experimental brain tumor vaccine coaxes the immune system to attack diseased cells only. Trials on other cancers may follow.

By Bruce Goldman, Special to The Times

January 14, 2008

CANCER patients and physicians are always looking for therapies free of side effects. But the standard treatments available to them -- chemotherapy and radiation -- typically work via a shotgun approach, indiscriminately killing all rapidly dividing cells whether they're cancerous or not. A long-held notion that the immune response might, in some practical manner, be harnessed to target cancer cells while sparing the rest is now being put to the test.

An experimental vaccine is now in multi-center, late-stage trials for treatment of glioblastoma, the most common brain cancer in adults. If the therapy lives up to its promise, it could potentially be used for other cancers as well.

Magnetic Resonance Imaging

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- Tumors put to the test

Glioblastoma, which strikes more than 10,000 adults per year in the United States, is a particularly aggressive form of brain cancer: Only one-half of patients survive for one year, even after radiation treatment and surgery to remove as much of the tumor as possible. The recent introduction of temozolomide, a chemotherapeutic drug, to the arsenal has added barely two months of survival to patients' lives.

Normally, we think of vaccines as prevention measures that enable our immune systems to pounce on bacteria or viruses the minute they strike. In this case, however, the new vaccine -- which goes by the experimental name CDX-110 -- is designed to kick-start an immune assault on an existing tumor.

So far, CDX-110 has been administered to almost 70 people, with virtually no side effects, according to Dr. John Sampson, a neuro-oncologist and brain surgeon at Duke University in Durham, N.C., who has been working on the vaccine.

The vaccine is designed to treat a certain subtype of glioblastoma that is present in 25% to 40% of cases. Tumors of this sub-type have a mutant protein known as EGFRvIII studded on the surface of many of their cells -- a twisted variant of a normal protein called EGFR. The normal EGFR is widely distributed on cells in the body and will stimulate division of the cell when it receives the correct hormone signal.

The mutant protein EGFRvIII, however, has an altered structure that sticks it in the "on" position permanently -- relentlessly triggering cell division, causing out-of-control, cancerous growth. Glioblastoma patients testing positive for EGFRvIII have a bleaker prognosis than those who don't. Virtually no EGFRvIII-positive patient survives two years, versus about 15% of those who are negative.

But there's an upside. The very uniqueness of the EGFRvIII protein has allowed scientists, in theory, to design a vaccine against tumor cells and only tumor cells.

The vaccine, designed by Sampson and Dr. Amy Heimberger, a brain surgeon at the M.D. Anderson Cancer Center in Houston, is fairly simple: It consists of a small fragment of EGFRvIII with a slight structural modification plus a couple of substances known to enhance the immune response. The theory: The body's immune cells, after being exposed to this protein, will launch an attack on EGFRvIII-positive cells but -- unlike chemotherapy or radiation -- will spare hair, skin, intestinal lining and immune cells.

In a just-completed study led by Sampson and Heimberger, 23 glioblastoma patients underwent radiation treatment and then surgery to excise all but traces of their tumors, followed by a single dose of the anti-tumor drug temozolomide.

Next, they received three biweekly injections of the experimental vaccine. Vaccine injections were continued monthly until patients' tumors returned, as they almost invariably do.

The results, which are not yet published, were encouraging, Heimberger says. Half of the patients survived for more than 30 months after treatment, versus the 12 months expected for patients treated only with radiation and surgery. And 65% were still alive after two years, compared with the almost-zero two-year survival rate predicted for this class of patient. Several have survived more than three years, Heimberger adds.

Typically, tumors recur within six months in patients given standard treatment, but with vaccine treatment, recurrence was delayed almost 15 months, Sampson says.

CDX-110 is not the only cancer vaccine in clinical trials, but it may be the first truly tumor-specific one that can be easily mass-produced. (A few other "personalized" vaccines, which aim at protein targets that differ from one patient to the next, are also under clinical investigation, but identifying and manufacturing vaccines on a one-off basis is inherently costly.) The prospect of a first-ever "off the shelf" cancer vaccine applicable to large numbers of patients has drawn the attention of investors as well as investigators.

Celldex Therapeutics, a New Jersey-based biotechnology company that has licensed rights to the vaccine from its Duke inventors, is sponsoring a larger, randomized clinical trial of 90 glioblastoma patients. Enrollment is underway in nearly a score of medical centers across the U.S., with UCLA planning to start enrollment Wednesday, and UC Irvine and USC further down the road. (For a list of centers recruiting patients, see www.celldextherapeutics.com).

If CDX-110 continues to slow the return of patients' tumors, the trial will expand to a 360-patient clinical study to more thoroughly test the treatment's promise, says Tom Davis, chief medical officer of Celldex.

The vaccine may prove useful in more than just treatment of glioblastoma, Davis says, because the abnormal protein EGFRvIII turns up in several other tumor types, including cancers of the breast, lung, head and neck. A success in glioblastoma could thus portend a similar vaccine approach to these cancers as well, although trials for those other cancers won't take place until a large-scale, controlled glioblastoma clinical trial has reported success.

Sampson and Heimberger caution that the therapy, although promising, is not a panacea. Sooner or later, solid tumors typically evolve sophisticated mechanisms to shut down the immune response, meaning that only very early-stage patients or those whose tumors have been all but eliminated by surgery can hope to benefit from the vaccine.

Even a successful vaccine won't be applicable to the majority of glioblastomas that are EGFRvIII-free, Heimberger says. And even if they are applicable, most patients' conditions still eventually worsen, because EGFRvIII-positive glioblastomas also contain other cells that aren't killed by the vaccine.

But getting rid of EGFRvIII cells seems to take some of the fight out of whatever tumor cells do remain, slowing their return. And the extra time is precious. In 2002, a diagnosis of brain cancer forced Amy Pomykal, then Mrs. Dallas County, out of the Mrs. Texas pageant. "They told me, 'Go home and have a good life for a couple of months until you die,' " says the American Airlines flight attendant. Her search for a better prognosis led her to volunteer in 2003 for the early-stage vaccine trial.

Four-and-a-half years later, with an 18-month-old son at home and another child due in March, she is not only disease-free, according to her twice-yearly brain scan, but working extra hours at the airport. She says her only restrictions are scuba diving and roller-coaster riding -- a prohibition she breaks annually at the Texas State Fair.

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