Spring 2010

The power within

In the search for cancer cures, it turns out that some of the most powerful answers have been inside us all along

Immunotherapy header
By Ignacio Lobos

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Somewhere in Oregon, a man now in his mid-50s goes about his business like any other person. If you were to meet him, nothing in his demeanor would signal that at one point he didn’t have much of a chance of living.

There would be no telltale blotches on his skin—the crude sketches that mapped out his skin cancer. No evidence that at one time the disease had dug itself deeply into his body, invading a groin lymph node and one of his lungs.

And there would be no way to know that during one key moment he fought back with renewed vigor, vanquishing the malignant cells from sight without the painfully blunt weapons that have been typical in cancer care for many decades. No chemotherapy. No radiation. No long and painful hospital stay.

Dr. Fred Appelbaum
Dr. Fred Appelbaum
Since his involvement in advancing bone marrow transplantation during the Hutchinson Center's early days, Appelbaum has become an internationally recognized leader in research that improves treatments for blood cancers.
The PET and CT scans that followed showed no presence of the skin cancer that had been consuming him. His late-stage melanoma, the deadliest of skin cancers, had gone into long term remission. And here’s the amazing part. His own cells, his own immune system, the very system that earlier had failed to put the brakes on his cancer, saved his life.

Of course, he didn’t do it all on his own. The chain of events that prompted his recovery was put into motion about two years ago by a team of researchers led by the Hutchinson Center’s Dr. Cassian Yee, who studies the cancer-fighting abilities of certain cells in the immune system. Yee had found a way to boost the man’s immune cells to improve his odds against the cancer, and the results surprised even him: The cells rapidly obliterated the cancerous ones until none could be detected.

Now, a skeptic might assume—and correctly—that one cured person does not a cure make, but that didn’t stop the story of the Oregon man from being reported around the world. In the emerging field of immunotherapy—in which a person’s own immune system is manipulated and amplified to better fight disease—this was a spectacular achievement. Yet, even Yee tempered the growing excitement. This single successful therapy would have to be replicated many times before it could be considered a standard treatment against cancer.

Hutchinson Center researchers have been at this junction between life and death before. The Center’s Dr. E. Donnall Thomas, who sought to perfect bone marrow transplantation to treat deadly leukemia and other blood cancers, stood at this very threshold more than 30 years ago.

 

Not everyone believed that Thomas’ research would lead to successes, but Dr. Fred Appelbaum was immediately hooked when as a sophomore in medical school in 1970 he first read Thomas’ seminal paper on the potential for bone marrow transplantation.

Dr. Cassian Yee
Dr. Cassian Yee
By extracting rare disease-fighting T-cells from the blood, multiplying them, and infusing them back into the patient's body to annihilate cancer cells, Yee and his colleagues are establishing themselves as leaders in this promising new therapy.
“I’m 63 now and bone marrow transplantation has gone from something that was an idea to something that will be done 60,000 times around the world this year to treat patients. It’s gone from an idea that it may work in one patient—maybe two—to something that has been used to treat 900,000 people so far,” said Appelbaum, who oversees all immunotherapy related initiatives at the Hutchinson Center.

And because of the power of the immune system, “we have thousands of people who are walking around cured of leukemia and lymphoma,” he said.

That’s why the Oregon man, and a second man who has been cancer-free for more than a year after a similar procedure conducted by Yee’s team, are so important. They have shown us what is possible—that boosting the immune system to fight many other types of cancers, to cure them, is within sight. The latest research has shown that immunotherapy may soon work consistently against melanoma and renal cell (kidney) cancer. At the same time, important advances are being made against breast cancer—with ovarian, colon and pancreatic cancers and sarcoma as other potential targets for an enhanced immune system.

“I certainly hate to overpromise,” Appelbaum said. “But I would be very disappointed if in five years we haven’t taken at least one or two diseases where our immunotherapy research is now just being tried on some solid tumors and not see it translated into a therapy that is being routinely used against them.”

Among the millions of enemies, cancer

Dr. Oliver Press
Dr. Oliver Press
As an oncologist and radioimmunotherapy researcher, Press is one of the world's leading lymphoma researchers. He pioneered the use of radiolabeled antibodies to blast cancer cells with high-dose radiation while sparing normal cells.
Most cancer treatments extract a high toll from patients. Chemotherapy and radiation kill cancer cells but also ravage healthy ones. The often-toxic treatments are painful and carry many complications, many of which follow patients for their entire lives. Surgery carries a high risk, too—and it’s not an option for some cancers that have invaded extremely sensitive areas, such as the brain and the spine. Many therapies also carry a high rate of cancer recurrence.

Immunotherapy has the potential to change cancer care for thousands of patients, to make it less toxic and less invasive, with a much higher rate of success than conventional treatments. That optimism has grown from a greater understanding of the immune system and many positive results at the Hutchinson Center.

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The Center’s Program in Immunotherapy counts more than 30 researchers, including several world experts in their respective fields.

“Because of our historic interest in the immune system and our pioneering research that led to bone marrow transplantation, we have had a stronger focus on immunotherapy than any other cancer center anywhere, and we have populated our labs with leaders in the field,” Appelbaum said.

Described most simply, the immune system is a 24/7 sentinel that goes to work when a virus, fungus, parasite or bacterium enters the body. This sentinel is as good as the sum of its parts: an intricate network of multiple organs, cells and other molecules working together to recognize and destroy invaders.

Dr. Phil Greenberg
Dr. Phil Greenberg
Greenberg developed the principles of T-cell therapy and pioneered its use for treating blood cancers and preventing infectious diseases.
“The body has a remarkable ability to see things that are not its own, not itself, and react against them,” Appelbaum said. “And there are enormous numbers of potential pathogens—millions and millions of them. It’s simply extraordinary that your body can see all of those as being different and yet see itself and not react against itself.”

As good as it is, the immune system still can’t cope against some viruses such as HIV—a wily enemy that so far has found a way to circumvent our defenses.

And on its own, the immune system doesn’t do a good job against cancer, even though it recognizes many types of malignant cells and kills them before they become a problem. Because every cancer cell was once a normal cell with a few mutations in its DNA, the immune system sometimes doesn’t recognize cancer cells as being different. Instead of killing them, it tolerates their presence. Cancers also have a number of strategies to evade the immune system.

That’s why the Hutchinson Center’s immunotherapy strategy rests on a couple of key principles: boost the power of the immune system so it won’t tolerate cancer cells, and unmask these malignant cells so they can no longer hide and multiply out of sight.

“With the advances that we have seen and our understanding of the immune system in terms of what it sees, how it sees it, what it kills, how it kills it, how it maintains memory, what blocks it—in every one of these areas, we know so much more than we knew just a few years ago,” Appelbaum said.

A multiplying effect

The use of T-cells— a type of white blood cells— against cancer has been one of the most promising immunotherapy techniques to emerge from bone marrow transplantation research at the Hutchinson Center.

Dr. Stanley Riddell
Dr. Stanley Riddell
Riddell and colleagues are making sophisticated strides in lending immunotherapy more staying power. They've pioneered a method of fortifying the body with rare central memory T-cells to fight leukemia and potentially many other cancers.
Until recently, our understanding of T-cells had been limited. We knew that there were killer T-cells, helper T-cells and suppressor T-cells floating through the bloodstream and the lymphatic system, each with their assigned tasks against invaders.

But we didn’t know how they interacted with one another, and with other elements of the immune system, to fight disease. Isolating and growing specific types of cancer-fighting cells in a laboratory setting also was technically difficult. But researchers have patiently worked to increase their understanding of T-cell behavior, uncovering the presence of specialized cells that are transforming the fight against cancer.

Yee has been at the front of the pack, showing that it’s possible to infuse patients with billions of their own helper T-cells to put solid tumors into long-term remission—without the aid of radiation or chemotherapy. He did it with his Oregon patient after his team identified and isolated one particular type of T-cell that had not given up the fight against the cancer but was greatly outnumbered. Yee’s lab took a few of the patient’s CD4+ T-cells, multiplied them into an army of 5 billion, and infused them back into the patient.

“Our T-cell research program has gained a lot of momentum recently, both from the research aspect and with funding from donors and the National Institutes of Health,” Yee said. “We continue to work in melanoma, evaluating methods to improve T-cell therapy, but have also made inroads into other cancers through a number of preclinical studies that may translate into clinical trials.”

Yee isn’t alone in making major T-cell breakthroughs at the Center. Dr. Stanley Riddell is perfecting a method to produce large quantities of a type of T-cell with a long life and a long memory. This technique is important because T-cells don’t tend to live very long, and a cancer can return if an immune response is not sustained. If we can coax these special “central memory” T-cells to stay in the body for a long time and remember cancer, immunity could last a lifetime, much like it does when someone is vaccinated against certain viruses. This approach could help prevent cancer recurrence.

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“Our goal is to educate T-cells to do the right thing,” Appelbaum said. And the right thing is to kill cancer.

A vaccine against cancer

Dr. Mary “Nora” Disis, a national leader in cancer-vaccine research, said her area of expertise is also making major strides within the field of immunotherapy.

Dr. Nora Disis
Dr. Nora Disis
Disis is a national leader in solid-tumor cancer-vaccine research and a lead scientist at the University of Washington and the Center. She combines vaccines and T-cell therapy for breast and ovarian cancer.
She points to this past year as a sure sign of progress, when three advanced clinical studies showed the benefits of vaccination in patients with prostate cancer, follicular lymphoma and melanoma.

“When people ask why it’s taking so long to come up with effective therapies, I’d say we’re here. This is it,” Disis said. Vaccines have already shown great promise in preventing certain cancers from developing in healthy people. One example is the groundbreaking human papillomavirus vaccine against cervical cancer, which was developed in part through research from the Hutchinson Center. Now vaccines based on immunotherapy have the potential to stop the recurrence of cancer for many types of solid tumors—and with tolerable or no side effects.

Traditional immunizations work by helping the immune system develop resistance to a weakened or dead form of a microbe. Then, if there’s contact with the live germ or virus, the immune system knows how to fight it off. But cancer cells often don’t induce a strong response from the immune system. Disis and others are working to change that picture.

A focus of their work is therapeutic vaccination, which is designed to treat an illness after it has been acquired. That’s an important distinction for cancer patients. The goal of a therapeutic vaccine is to provoke a stronger and faster response from the immune system to prevent the recurrence of cancer. Such a vaccine would be a lifesaver for women diagnosed with invasive breast cancer and ovarian cancers, which have high recurrence rates. About 30 percent of women diagnosed with invasive breast cancer will have recurrences within five years, and 80 percent of women treated for ovarian cancer relapse after the first treatment.

Therapeutic cancer vaccines also may increase survival times, delay the spread of the cancer, and help to maintain or improve patients’ quality of life.

Disis has focused her work on patients whose tumors have responded well to surgery and therapies but whose chances of recurrence are high. One of her trial vaccines stimulates the patients’ disease-fighting response by targeting a protein called H2N, which is found in higher levels in some breast and ovarian cancer cells.

“Our goal is to create a vaccine that will activate immunity to very high levels very rapidly against the H2N protein,” Disis said. Results have been promising. In early clinical studies of patients with metastatic breast cancer, 40 percent were still alive nine years after vaccination.

In a separate study by her team, late-stage breast cancer patients taking the drug Herceptin—a group whose average survival is 18 to 23 months—were also vaccinated. More than 80 percent of the patients were alive three years after vaccination, and 40 percent did not experience disease recurrence.

Dr. Tia Higano
Dr. Tia Higano
A prostate cancer oncologist at SCCA, Higano leads many clinical studies in prostate cancer patients using cancer vaccines as well as other new immunotherapy agents.
Dr. Tia Higano, a prostate cancer specialist at the Seattle Cancer Care Alliance (the Hutchinson Center’s clinical arm), is making strides against late-stage prostate cancer with another type of test-trial vaccine called Provenge.

In a study of about 500 men with advanced prostate cancer who had stopped responding to hormone-blocking treatments and who had few other treatment options, the vaccine lengthened survival by an average of four months. While certainly not a cure, the increase in survival is double the benefit of the only approved treatment to date—a chemotherapy drug—for men with advanced prostate cancer. Despite the modesty of the results, they still represent a major leap in vaccine therapy, Higano said.

“If you asked most of us 10 years ago if we thought therapeutic vaccines would have a role in any solid tumor, we would have said probably not. We now have a better understanding of the immune system and we see how powerful it can be when you’re trying to treat a tumor,” she said.

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Targeted therapies

There’s another major player in immunotherapy: antibodies, proteins produced by the immune system to fight germs, viruses and other invaders. The hallmark trait of antibodies is that, much like a guided missile, they go after an extremely specific target. They’re capable of directly fighting cancer cells—but not very good at it.

Dr. Hootie Warren
Dr. Hootie Warren
Warren and colleagues are trying to determine if stem cell transplants may help to fight an advanced form of kidney cancer that is almost impossible to cure with existing therapies.
One proven technique involves engineering special antibodies that, when injected in a patient’s bloodstream, know how to find their way to cells associated with a particular kind of cancer and attach themselves to the rogue cells. The antibody’s presence, in turn, flags the diseased cells for destruction by the immune system.

Hutchinson Center researchers have been pioneers in this area of research as well. In 1997, Dr. David Maloney and others earned government approval for the first antibody-based therapy to fight non-Hodgkin’s lymphoma.

The Center also played a key role in testing a breakthrough antibody-based drug that is armed with a cell-killing agent thousands of times more powerful than typical chemotherapy. Because the antibodies act as homing devices, seeking out malignant cells and depositing a direct hit of toxic chemicals, the drug manages to spare healthy cells. Since its approval in 2000, this drug known as Mylotarg has represented one tool for treating older adult patients with relapsed acute myeloid leukemia, one of the most fatal and serious forms of the disease.

More recently, researchers have successfully coupled another weapon to antibodies: radioactive materials that deliver a targeted dose of radiation to cancer cells. Radioimmunotherapy is the basis for the drug Bexxar, which received Food and Drug Administration approval in 2003 for treating non-Hodgkin’s lymphoma. Combined with stem-cell transplantation, radiolabeled antibodies, as they are known, have produced some of the best lymphoma cure rates in the world.

“I have patients that I treated 25 years ago, and they’re still here and they’re cured,” said Dr. Oliver Press, an oncologist who has studied radioimmunotherapy at the Center for more than two decades and was a key player in Bexxar’s approval. “It’s exhilarating.”

Dr. Thomas Spies
Dr. Thomas Spies
Important observations over the years by Spies and his Hutchinson Center laboratory are improving our understanding of how tumor cells sidestep detection by the immune system, allowing the cancer to grow.
A dramatically better approach may soon be available. Press and colleagues have begun laboratory tests of a method known as pretargeting, with 100 percent cure rates in mice so far. This multistep delivery method allows five times more radiation to specifically reach the cancer than with standard radiation—while avoiding healthy tissue. Pretargeting has proven especially important for treating blood cancers, which are dispersed throughout the body and thus have been harder to target than solid tumors.

But cancer is a complicated disease with many weapons at its disposal. One of the reasons that so many people fall victim to cancer each year is that tumor cells are skilled at evading our body’s natural defenses—in essence, flying beneath the immune system’s radar.

This perplexing problem has captured the attention of Center researchers, led by Drs. Thomas Spies and Veronika Groh. In a key discovery, they found that in the later stages of certain cancers, tumor cells produce massive amounts of molecules called MIC, which serve to blind the immune system to the cancer’s presence, thereby stifling the body’s cancer-fighting ability. The phenomenon is like “putting a wet blanket on a fire,” as Spies puts it.

In the future, it may be possible to develop new antibody based drugs that neutralize the ability of these molecules to block our immune system’s responses and prevent tumor cells from evading detection, growing unchecked.

Dr. Marc Cheever
Dr. Mac Cheever
A catalyst for moving science out of the lab and into the clinic. Cheever has made seminal contributions to T-cell therapy and cancer vaccine efforts.
As researchers continue to unravel the mysteries of the immune system, there’s greater urgency to move their work from the lab into the clinic.

“Because of Don Thomas’ legacy, we have a compulsion to take the work of our researchers into the clinical setting—we have the expertise and the history,” Appelbaum said. “In the past, we have been often disappointed because the hurdles seemed daunting and we didn’t understand enough to surmount them. But we have renewed enthusiasm that the time is right to step on the gas and prove that our hypotheses about immunotherapy are correct.

“A cure isn’t enough. We need to cure without extracting such a toll from our patients. Immunotherapy offers us that promise.”

Colleen Steelquist and Anne Broache contributed to this article.

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