As the body's staunch protector, the im- mune system is well known for its ability to battle infection and repair wounds. But scientists have long questioned how or even whether this biological defense system shields the body from one of nature's most aggressive attackers: cancer.
The immune system's aptitude for sweeping the body clear of budding tumors continues to fuel scientific debate. Yet that has not stopped researchers from mining this potential for a novel array of cancer treatments - collectively known as immunotherapy - that is predicted to have fewer side effects than conventional chemotherapy.
Already, researchers at Fred Hutchinson have tapped into the immune system's curative powers to develop and test new therapies for leukemia, melanoma and viral infections.
Now, scientists at the center and the University of Washington hope to extend this approach for treatment of breast cancer, the second leading cause of cancer deaths in women.
The effort is funded through two gifts from the Avon Foundation, including $2.5 million for breast-cancer research that included an initiative in breast-cancer immunotherapy and $1.25 million for investigation of the immune response to breast cancer and to develop immune-based therapies.
Dr. Stan Riddell, an investigator in the Clinical Research Division, and Dr. Nora Disis, UW associate professor of medicine, lead the project, along with Dr. Wei Wang, an immunotherapy fellow in Riddell's lab, and colleagues in the Breast Cancer Research Program at both institutions.
The Avon funding also fosters interactions between Seattle scientists and investigators at The Johns Hopkins University who are engaged in related breast-cancer research.
Riddell, whose lab is a leader in the development of immunity-based therapies, said the power of this approach for treating cancer is most convincingly illustrated by a relatively new leukemia treatment known as the mini-transplant.
Developed by Dr. Rainer Storb and colleagues, the technique relies on the cancer-fighting properties of immune cells from a tissue-matched donor that are infused into a cancer patient. Although not completely free of side effects, the treatment spares patients from high doses of radiation and chemotherapy.
"The lesson from the mini-transplant is that you don't necessarily need to give toxic chemotherapy to cure cancer," Riddell said. "The challenge now is to apply the approach in an autologous setting, meaning that rather than relying on a donor to supply the immune cells, the cancer-fighting cells would come from the patient."
Both strategies rely on the immune system's ability to discriminate between "self" and "non-self" tissue, an activity carried out by a class of white blood cells known as T cells.
When a T cell recognizes another cell in the body as foreign - because a cell is infected with a pathogen, displays abnormal markers characteristic of cancer or is transplanted from another individual, for example - it initiates a process that targets that cell for destruction.
Subtle tissue-type differences
In the case of the mini-transplant for leukemia, scientists believe that donor T cells fight the disease because of subtle differences in tissue type between patient and donor. The donor immune cells see the patient's leukemia cells as foreign because of their unique tissue signature, rather than because they produce cancerous proteins.
The mini-transplant can treat blood cancers, since donor cells are delivered directly to the cancer site. Though the technique also has shown signs of success with a form of kidney cancer, much remains to be learned about whether this approach will be effective for cancers of other organ systems.
As an alternative, immunotherapy experts like Riddell, and colleagues Drs. Phil Greenberg and Cassian Yee, have turned to an approach that encourages a patient's own immune cells to attack tumors or virus-infected cells.
In this strategy, known as adoptive T-cell therapy, researchers extract white blood cells from a cancer patient and expose them to proteins made in abundance by tumor cells. Scientists then identify the few T cells that recognize the tumor proteins and stimulate these T cells to divide, generating a large population of cancer-fighting cells that can be transfused back into the patient.
Ideally, this unique population of T cells will find its way to the tumor site and destroy cancer cells.
To develop adoptive T-cell therapy for breast cancer, Riddell and Wang must first identify appropriate proteins made by breast tumors that could serve as targets for cancer-fighting T cells. Such proteins could be produced exclusively by tumor cells or could be normal proteins made in abnormally large quantities relative to healthy cells.
Riddell said that although there is evidence to support the general theory that the immune system recognizes tumors, little is known specifically about whether such innate surveillance acts upon breast tumors.
"That's why breast cancer presents an interesting challenge," he said. "There isn't much evidence for whether T-cell recognition of tumor proteins occurs naturally in breast cancer. So we're really beginning our effort with some basic research studies to identify and characterize unique or overabundant proteins made by breast tumors and to learn whether the surveillance system is dampened in some way in patients with cancer."
Direct study of tissue
In Riddell's lab, Wang's initial approach is to evaluate T-cell response to candidate proteins that have been linked to breast cancers. He also investigates the immune responses at the tumor/immune cell interface by directly examining breast-tumor tissue.
The studies depend on access to surgical specimens, provided through the Breast Specimen Repository established by Dr. Peggy Porter, head of the Breast Cancer Research Program. Other immunologists at the center who contribute to various aspects of the project include Yee, Greenberg, and Drs. Thomas Spies and Veronica Groh, all of Clinical Research.
As is the case for vaccine-based strategies, adoptive T-cell therapy for breast and other cancers likely will be most effective on patients who first undergo other treatment, including surgery, to remove the bulk of the tumor. Immunotherapy then could be applied to attack residual traces of cancer.
"The holy grail for breast cancer is to identify the best tumor antigens (proteins that can be recognized by the immune system) to serve as immunotherapy targets after mastectomy or lumpectomy," Riddell said.
While that may be the ultimate goal, he admits that the problem is a challenging one that is just beginning.
Still, Riddell is optimistic that research on the immunology of breast cancer will pave the way for development of future therapies.
"There's a lot of excitement in the field," he said, "and here in Seattle, we have a group that's working collaboratively to probe many aspects of this complex process."
Disis lab develops vaccines to boost patients' immunity
A different approach to immunotherapy proceeds in the lab of Dr. Nora Disis, where she and colleagues develop vaccines designed to boost a patient's own immune system to recognize and fight tumor cells. Several years ago, her group demonstrated that patients do possess a weak but detectable, innate immune response to tumor markers that could be exploited for vaccine development.
One such vaccine that has shown promise in clinical trials for women with advanced breast cancer is targeted against HER2/neu, a normal protein that is overproduced in some breast tumors. The study's patients underwent therapy to remove detectable cancer and were vaccinated to prevent relapse.
Although a long-term, follow-up study is still under way, Disis said that as late as five years after the vaccination, immune response against HER2/neu could be detected in one patient's T cells, suggesting that vaccination could confer immunological memory for detecting recurrent cancer.
More recently, Disis identified additional tumor proteins suitable for vaccine development. Ultimately, she hopes to develop a single vaccine against multiple tumor targets, which would enable a patient's immune system to react against a broad array of breast-cancer cell types