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Precision punch to lymphoma

Ajay Gopal and colleagues use antibodies to deliver targeted, less toxic treatment to lymphoma's most vulnerable victims
Dr. Ajay Gopal
Dr. Ajay Gopal examines a patient at the Seattle Cancer Care Alliance. Gopal and colleagues work to improve treatments for non-Hodgkins lymphomas. Photo by Todd McNaught

One of cancer's cruelest ironies is that it mostly strikes older people, a group that is least physically able to cope with the side effects of treatment.

That means an oncologist who routinely cares for patients over age 60 must practice medicine like a skilled prizefighter, packing a precision punch to cancer cells while leaving the rest of the body unbruised.

This can be especially challenging when treating immune-system cancers like lymphoma, which often require heavy rounds of radiation and chemotherapy followed by a stem-cell transplant to knock the disease into remission. But oncologists like Dr. Ajay Gopal, an assistant professor of medicine at the University of Washington and an assistant member in the Clinical Research Division, are discovering that some of these lifesaving options can be delivered with a gentler touch.

Using antibodies that deliver a blast of radiation directly to cancer cells and drug regimens with fewer side effects, Gopal and colleagues hope to improve the quality of life for lymphoma patients young and old. This newer generation of therapies also benefits those whose disease has relapsed after initial therapy, another group less physically fit to withstand the side effects of treatment. His work builds on the pioneering efforts in this field of Dr. Oliver Press, also of the Clinical Research Division.

About 20 percent of Gopal's time is spent on clinical care at the Seattle Cancer Care Alliance and UW, where he is one of several lymphoma specialists. Yet even when he is not attending he spends much of his time with patients in the clinic, where he leads several clinical trials to test promising new lymphoma therapies.

"My job is to bring new ideas from the lab into the clinic—and to bring what we learn from patients back into the laboratory," he said. He works closely with Dr. John Pagel, Press, and other members of Press' lab, who have been leaders in adapting antibodies—infection-fighting proteins of the immune system—into anti-cancer bullets against lymphoma.

A disease on the rise

Lymphoma is a cancer that develops in immune-system cells known as lymphocytes. The disease is classified into two general types: Hodgkin's lymphoma, a highly curable cancer, and non-Hodgkin's lymphoma, of which there are multiple aggressive and slow-progressing forms. Gopal primarily treats patients with non-Hodgkin's lymphoma, a disease whose incidence has jumped over the last several years for unknown reasons—and is likely to increase even further in the future.

"More than half of non-Hodgkin's lymphoma cases occur in patients over age 60, a population group that is projected to grow from 12 percent today to 20 percent in 2030," he said.

Many non-Hodgkin's lymphomas are treated with high doses of total-body radiation or chemotherapy to wipe out the cancer cells, which also throw a powerful punch to healthy immune-system cells. Since patients can't survive with out an infection-fighting response, patients usually are given a subsequent infusion of their own immune-system stem cells, which are extracted prior to treatment and manipulated to remove as many cancer cells as possible.

Total-body irradiation also inflicts collateral damage on other vital organs, which means that doctors can't always give patients high enough radiation doses to wipe out very stubborn cancers—like many types of lymphoma—without risking severe, even fatal, complications. To get around this, Gopal and colleagues rely on antibodies to deliver radiation to lymphoma cells. Unlike the total-body irradiation typically given to patients before transplant, antibodies tagged with radioactive iodine target radiation directly to B cells, the immune-system cells from which many forms of lymphoma arise. Although these antibodies don't spare healthy B cells from radiation exposure, they don't inflict harm on the lungs, kidneys, skin or other organs. That means doctors can give patients higher radiation doses than what they could normally tolerate from a total-body blast.

In a study published last fall, Gopal and colleagues found that patients with relapsed follicular lymphoma who were treated with radioactive antibodies followed by a transplant with their own stem cells (known as an autologous stem-cell transplant) had a five-year overall survival rate of 67 percent. In comparison, patients who received total-body irradiation plus chemotherapy or chemotherapy alone followed by transplant had an overall survival rate of 53 percent. What's more, patients in the antibody group were nearly three times less likely to die from treatment-related complications.

Promising pilot study

The team also has made progress on what Gopal describes as one of the biggest challenges facing researchers in his field: an exceptionally tough-to-cure cancer known as mantle-cell lymphoma. Unlike other aggressive lymphomas, relapsed mantle-cell lymphoma is rarely cured by high-dose therapy followed by transplant.

"Mantle-cell lymphoma has the worst adverse characteristics of both aggressive and indolent lymphomas," he said. "It's fairly rare—only about 5 percent of lymphomas are mantle cell—but because of our expertise we see a lot of cases here."

In a recent pilot study of 16 patients, he and colleagues achieved overall three-year survival rates of 93 percent for relapsed mantle-cell lymphoma using the radioactive antibodies followed by chemotherapy and an autologous transplant. Disease-free survival during that time period was 61 percent, and no patients died from treatment-related complications.

Not every case of lymphoma is curable with existing treatments. But Gopal is exploring whether patients who have incurable slow-progressing forms of lymphoma could control their disease with drugs—similar to the way people with high cholesterol manage their condition by taking statins.

New drug therapies

Many patients with slow-progressing, or indolent, lymphomas are treated with Rituximab, a non-radioactive antibody that targets cancerous B cells with few side effects. Although about half of patients who receive this therapy go into remission, most will eventually relapse. The addition of chemotherapy to the regimen improves the response, but the drugs cause side effects.

"Patients can't take chemotherapy forever," Gopal said. "The idea is to find a medication that can be taken chronically in pill form with few or no side effects that allows patients to remain symptom-free and enjoy a good quality of life."

A promising option is a drug called fenretinide, which triggers lymphoma cells to self destruct—a property often lost in cancer cells—and has minimal toxic effects. In a recently published study done in collaboration with Dr. John Pagel, Gopal tested combination therapy with Rituximab and fenritinde in mice with lymphoma.

"The vast majority of mice were cured when the drugs were used together," Gopal said, a result he described as very exciting. "The next step is to test this in the clinic. Our hope is that patients will be able to manage their disease over the long-term with few side effects."

On another research front, Gopal is developing more easily tolerated chemo regimens for patients who have relapsed lymphomas.

"If a patient's disease returns after chemotherapy, some are treated with a different chemotherapy regimen followed by an autologous transplant," he said. "That second chemo regimen is often very intense and typically must be given in the hospital. We're trying to develop a regimen using a new generation of drugs that we hope will be just as effective but much gentler," he said. This therapy is currently being tested in a clinical trial through the Puget Sound Oncology Consortium.

Though there's unlikely to be a single knockout punch for lymphoma, these and other new treatment options add extra rounds to the fight, Gopal said.

"Our understanding of the biology and clinical aspects of lymphoma continues to expand, yielding new hypotheses, laboratory studies, clinical trials and ultimately novel effective therapies for this group of diseases," he said.

'Patients can't take chemotherapy forever. The idea is to find a medication that can be taken chronically in pill form with few or no side effects that allows patients to remain symptom-free and enjoy a good quality of life.'
Dr. Ajay Gopal, Clinical Research Division

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