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Focus: Cancer Treatment: Testing a Defense; Roswell Park Will Study Whether a Vaccine Can Trigger An Immune System Response to Cancer, Which Could Lead to Targeted, Less Toxic Treatments - And Maybe Prevention

Buffalo News


When Roswell Park Cancer Institute announced a new trial of an experimental cancer vaccine earlier this year, 5,000 people watched the event on the Internet, 4,000 called or emailed in the following days and nearly 1,000 people posted comments on Twitter.

All this for a small study that will enroll only 18 participants to gauge safety.

The intense interest reflected the major re-emergence of an idea that has intrigued medical scientists for more than a century - using the body's natural ability to defend itself against disease-causing organisms, the immune system, to treat and prevent cancer.

The immune system has trouble recognizing cancer cells as dangerous and does not act to destroy them. But decades of scientific insights, as well as the landmark approval in recent years of a few early-generation cancer vaccines, now strongly suggest that the body's defenses can be manipulated to attack cancer cells.

The survival benefit of the approved vaccines is modest - only a few more months than conventional therapies. The criteria for using them are narrow. And, they are wildly expensive, one costing $120,000 for one course.

But evidence is mounting that the concept can work and that other cancer vaccines under study around the world can improve on past versions.

It is the potential advantages of vaccines that make them so compelling - more targeted, less toxic, shorter treatments, the ability to keep the body on guard for cancer cells that reappear and the ultimate goal of using them to prevent cancers altogether.

"There is a slew of data indicating that an immune response can lead to better outcomes in cancer. The question is, how can we harness this power of the immune system?" said Dr. Kunle Odunsi, director of Roswell Park's Center for Immunotherapy and the new study's principal investigator.

Conventional vaccines contain harmless versions of microorganisms, such as the flu, that stimulate special cells, proteins and tissues in the body to identify and destroy viruses, bacteria and parasites. The immune system also develops a memory for these microbes, standing on guard in case the same foreign invaders infect the body in the future.

But cancer isn't usually about the body coming under attack from obvious enemies. Tumors arise from normal cells and so resemble normal cells, and the body is not designed to attack itself. Tumor cells also have ways to evade detection.

As hopeful as the idea of vaccinating to treat or prevent cancer seems, researchers face huge challenges.

A cancer vaccine must figure out how to educate the immune system to recognize the tumor cells or get the defective cells to look more suspicious. To be truly safe and effective, a vaccine must also bring about a long-term "memory" for the tumor cells it is designed to target and accomplish this without producing autoimmunity, a condition in which the immune system attacks the normal cells it is supposed to protect.

"There is a lot of promise. I tell people they need to be patient. The trouble is, I also know that when you have cancer, you can't be patient," said Dr. Candace Johnson, deputy director of Roswell Park.

That any of this is plausible goes back to the slow accumulation of observations over the last century. A turning point came in the late 1800s, when New York surgeon William Coley saw that his cancer patients did better when they suffered from bacterial infections.

Coley figured the infections triggered an immune response that shrank tumors. He was the first to systematically test the idea in a number of patients by injecting them with a vaccine made from bacteria.

Unfortunately, it wasn't clear how his vaccine worked, and his findings became overshadowed by the emergence of chemotherapy and radiation, which weaken the immune system, as standard treatments for cancer.

Now, hundreds of studies are under way to find the best strategies to stimulate an immune response against tumor cells, with the hope of producing vaccines that can treat or prevent cancers.

"We need to learn how to immunize before we learn how to vaccinate patients," said Dr. John Kirkwood, co-leader of the University of Pittsburgh Cancer Institute's Melanoma Program who is leading a number of clinical trials with cancer vaccines.

Progress is being made.

The U.S. Food and Drug Administration approved two vaccines, Gardasil in 2006 and Cervarix in 2009, to protect against infection by viruses that cause cervical cancer. However, cancer mostly is caused by defects in cells, not by viruses.

To date, the FDA has approved two immunotherapies for cancer - Provenge for advanced prostate cancer in 2010 and Yervoy for melanoma in 2011.

Provenge costs $96,000 but is viewed as a major achievement, being the first vaccine for a solid tumor. In a major study, the vaccine extended survival in advanced prostate cancer patients by a median of 4.1 months - from 21.7 to 25.8 months - although a newer analysis suggests the benefit may be 7.8 months. The median means the middle point in a group of statistics.

Researchers describe Yervoy, which costs $120,000, as more like a drug than a vaccine that releases the brakes that hold back the immune system from fighting cancer.

In a study cited by the FDA, Yervoy extended median survival to 10 months from nearly 6.5 months for patients who didn't get the drug, although 20 percent lived more than two years and some even longer. Yervoy is the first drug approved for metastatic melanoma in more than a decade, and the first to show increased survival among advanced skin cancer patients.

"What we're seeing is proof that the concept works," said Dr. Kelvin Lee, chairman of immunology at Roswell Park.

Roswell Park has been experimenting with a number of vaccine formulations based on a particular antigen associated with a lot of cancer cells but not found in normal cells except in the male testes.

An antigen is any substance that causes the immune system to produce antibodies against it. In this case, the antigen is a protein called NY-ESO-1.

In an early version of the vaccine, researchers used a fragment of NY-ESO-1, combined with a substance to irritate the immune system, to vaccinate 18 women with advanced epithelial ovarian cancer.

The vaccine induced a significant immune response by training special immune cells known as T cells to recognize NY-ESO-1 as foreign and attack it.

Most of the patients had a life expectancy of less than one year. The vaccine extended the time to recurrence of the disease to a median of 19 months, although some lived longer. One patient, 53-year-old Christine Sable, is still alive eight years later.

"I feel as though I helped medicine move forward a little," said the commercial real estate broker from Lancaster, Pa. "Maybe the day will come when chemotherapy seems barbaric, that we'll be able to prevent people from getting cancer in the first place."

Sable had undergone chemotherapy and major surgery after a diagnosis of advanced stage ovarian cancer. She went into remission but knew ovarian cancer was likely to return.

"I didn't want chemotherapy again," she said. "It was just so hard and debilitating."

Despite Sable's result, the vaccine showed limitations. The immune system's attacking cells, like tired soldiers on the battlefield, didn't maintain a prolonged effort to search out and kill NY-ESO-1 in all of the women, allowing tumor cells to evade detection and grow.

The latest trial uses a reformulated version of the vaccine that is custom made for each patient and accompanies it with a drug that researchers hope will train immune cells to remember to keep recognizing the cancer cells as dangerous.

Patients in the study donate blood. The researchers take the white cells, stimulate them to increase their numbers and then manipulate them to turn them into dendritic cells. Dendritic cells act like forward patrols in the body, recognizing invaders and recruiting killer immune T cells to attack. The dendritic cells are then coated with NY-ESO-1.

All of this happens inside a minivan-sized incubator manufactured specially for Roswell Park by BioSpherix Ltd., a company in Oswego County.

The incubator is essentially a clean room in a box that also can maintain cells under the same conditions found in the body. Its $350,000 cost is far less than the millions of dollars it would otherwise take to produce a vaccine, said Johnson.

After nine days, the dendritic cell vaccine is ready to be injected back into the patient, who will also receive rapamycin, a drug normally given to organ transplant recipients to suppress the immune system to prevent tissue rejection.

Other Roswell Park researchers found that they could use rapamycin in low doses to prevent the immune system from depleting its cancer-killing T cells quickly and see it as possibly helping create a long-term immune system memory for the type of tumor cells a vaccine is targeted to attack.

"The reason why some patients given these vaccines relapse is that their immune response is not long enough," said Odunsi.

The latest study is expected to show promise in treating patients with a variety of cancers, including bladder, brain, breast, esophageal, gastrointestinal, kidney, lung, ovarian and prostate, according to the researchers.

The advent of cancer vaccines prompts questions over their cost versus benefit.

Provenge and Yervoy, for instance, have extended life without shrinking tumors or changing the length of time the patient lives before the disease gets worse, both current measures of success in cancer studies.

Because the price of these two vaccines is so high, the benefit so modest and their use limited to patients with advanced cancer, the vaccines are rarely prescribed.

It's also unclear how vaccines will be used.

"There are so many variables to find the optimal strategies," said Odunsi, whose team is conducting a number of trials of NY-ESO- 1 simultaneously to address different questions.

Researchers envision using vaccines in combination with other drugs as an initial treatment and as a way to prevent relapse after standard therapy. The potential exists to use vaccines as a treatment in patients with earlier stages of cancer, although this will require very costly and difficult studies before it becomes a reality.

The ultimate goal is to design vaccines to prevent some of the many different types of cancer.

"We're in a renaissance in immunotherapy," said Lee. "We've learned how to grow immune cells and re-engineer them. This is where the technology is headed, and it's exciting."


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