S T A N F O R D M E D I C I N E

Volume 18 Number 2 Fall 2001
index

Related Stories:

Stronger and gentler:
How radioimmunotherapy works

Assessing radioimmunotherapy:
Stanford is a leader
in initiating clinical trials.

The hunt is on
by Krista Conger
Stanford researchers lead efforts to develop cancer treatments combining the power of radioactivity with immunotherapy


Sharon Apel discovered her cancer by accident. She had been feeling tired and run-down, but the 38-year-old Kansas City resident wrote off her symptoms as an unavoidable side effect of holding down a full-time job and caring for her three young children.

In 1985 the registered nurse attended a workshop to learn how to use specialized ultrasound equipment to view the interior of a patient’s carotid artery. The trainees started out practicing on each other. But when Apel’s turn came, her ultrasound didn’t look normal: She had a huge clump of lymph nodes in her neck.

“I knew what it was as soon as they told me,” says Apel, who had worked in the intensive care unit of a hospital in Kansas City. A lymph node biopsy confirmed the diagnosis: non-Hodgkin’s B-cell lymphoma. The cancer had spread to lymph nodes along her aorta and in her groin. Her doctors told Apel that she had a life expectancy of five to 10 years.

“My goal was to see all of my kids graduate from high school,” she says. But 18 months into her first chemotherapy-induced remission, she started getting night sweats. The cancer was returning. Over a period of 10 years, she had six separate rounds of chemotherapy. Every cancer-free period was a little bit shorter than the previous respite — her lymphoma cells were figuring out how to evade each successive round of drugs. By 1995 she knew she was running out of time, but her determination didn’t falter. She decided to travel to Stanford Hospital to try an experimental treatment called radioimmunotherapy.

The Food and Drug Administration is now reviewing the experience of Apel and other participants in clinical trials conducted at Stanford and several other institutions nationwide. As they weigh the pros and cons of approving the treatment, thousands of people are diagnosed with lymphoma each year in this country.

The disease is classified into two general types, Hodgkin’s and non-Hodgkin’s lymphoma. Apel’s non-Hodgkin’s lymphoma was made up of B cells, a type of cell that plays an important role in immune responses. Her B cells had begun dividing uncontrollably. These malignant cells can overwhelm the immune system and involve a variety of organs and tissues including lymph nodes, spleen, bone marrow and eventually even organs such as the liver, the lungs and the brain. The cancer’s progress may be slow but is often inexorable; only about half of the 50,000 people diagnosed each year in this country with this type of lymphoma are alive five years later.

As Apel had discovered, both Hodgkin’s and non-Hodgkin’s lymphomas can be fairly sneaky cancers — patients frequently have no obvious symptoms until the disease has spread throughout the body. The most common noticeable effect of the uncontrollably replicating cells is a painless but persistent swelling of lymph nodes in the neck, under the arms, or in the groin. Other symptoms can include fatigue, night sweats, unexplained fevers, weight loss and a feeling of abdominal fullness caused by swelling of the spleen, liver or abdominal lymph nodes.

In the early stages, some kinds of lymphoma may be confined to just one or two lymph node regions and may be treated successfully with radiation. Other kinds of lymphoma require initial treatment with chemotherapy — potent drug concoctions intended to kill cancer cells wherever they may be hiding in the body. For most patients, the dearth of easily recognizable symptoms means that the cancer is often discovered after it has already involved multiple lymph node groups, the spleen and/or the bone marrow. In these cases, physicians use chemotherapy, sometimes in combination with radiation therapy, which may send the cancer into remission. But for lymphomas like Apel’s, this response is usually temporary.

When the cancer recurs, a new round of chemotherapy with a different combination of drugs is used, but eventually the doctors begin to run out of drugs that will be effective and tolerable.

“These patients are generally considered to be incurable,” says Susan Knox, MD, PhD, associate professor of radiation oncology. “When patients start failing chemotherapy, subsequent responses to new regimens tend to be less good, and of shorter duration.”



Susan Knox


Viola Uyeda knows this firsthand. In 1988 the then 62-year-old Carmel resident was also diagnosed with non-Hodgkin’s B-cell lymphoma. Over the next eight years she tried everything to beat the disease — including several rounds of chemotherapy.

“My hair fell out twice. That’s when I found out my head wasn’t lopsided,” jokes Uyeda. “It gave my husband and me something to laugh about.”

But despite her positive attitude, her cancer kept coming back. In 1996 she came to Stanford Hospital to be part of a clinical trial testing a new treatment for her disease. There she met Knox.

Knox, a tall woman with a friendly face, is a Stanford veteran. She received her MD from Stanford in 1985 and completed her residency and fellowship in radiation oncology at Stanford in 1990. She joined the Stanford faculty in 1990 and is now an associate professor in radiation oncology. Soon after her appointment, Knox worked with oncology professor Ronald Levy, MD, and radiology professor Michael Goris, MD, PhD, to initiate a variety of clinical trials to test a new treatment for advanced non-Hodgkin’s lymphoma as well as solid tumors.

A powerful combination

The new treatment was called radioimmuno-therapy, a long word for a sophisticated approach to fight cancer. The technique had sprouted from Levy’s earlier work on monoclonal antibodies — the Y-shaped molecules used by the immune system to fight infection. Like Cinderella’s slipper, which fit only one girl at the ball, each antibody is tailored to recognize and stick to a unique three-dimensional shape. The target shapes are usually clumps or pieces of proteins from foreign invaders like bacteria or viruses. When an antibody binds to its target, it marks the invader for destruction by the body’s immune system.

In the 1980s, Levy began to experiment with monoclonal antibodies — a vast, single-minded army of antibodies that all recognize the same shape. He realized that if he could generate monoclonal antibodies that would bind only to tumor cells, he could harness the body’s immune system to help fight cancer. The trick lay in finding a way of differentiating the cancerous cells from the innocent bystanders.

Levy realized that all mature B cells, including those that run amok in lymphoma, express a unique protein label called CD20 on their surface. Like a nametag slapped on at a party, the CD20 label can be used to pick the renegade B cells out of a lineup of all the cells in the body. Antibodies that specifically recognize CD20 latch onto B cells throughout the body and target them for destruction. The fact that non-cancerous B cells also express CD20 is not as big a problem as it might seem because the body can generate more from non-CD20-bearing precursors.

The tactic seems effective. About 50 percent of advanced non-Hodgkin’s lymphoma patients participating in clinical trials of an anti-CD20 monoclonal antibody called rituximab have experienced at least some improvement in their cancers. Rituximab is now being studied as a front-line defense against newly diagnosed non-Hodgkin’s B-cell lymphomas, alone and in combination with various chemotherapy protocols.

The treatment that Knox, Levy, Goris and others were testing uses a similar approach, but with a twist. Instead of relying exclusively on the body’s immune system to destroy cells bearing the CD20 label, radioimmunotherapy delivers a deadly package directly to the lymphoma cells — a radioactive molecule that kills not only its target but also cells within a surrounding area about the size of a large pencil dot. The ability to kill neighboring cells means not every cancer cell needs to be bound by an antibody; odds are that if you’re a member of a small clump of lymphoma cells and the antibody seeks out even one of your klatch, your own chances of escaping are relatively low.

Targeting CD20-bearing cells for destruction limits the damage done to normal tissue, as does the researchers’ practice of using molecules that emit a particular type of radioactivity, called beta rays. Unlike gamma rays, which can travel through your body, beta rays travel only about 1 to 2 millimeters. But their capacity to smash into and destroy the DNA of nearby cells makes them effective close-range killers. Popular choices for beta emitters for radioimmunotherapy include 90-yttrium, a pure beta emitter, and 131-iodine, which emits both beta and gamma rays.

The Stanford researchers expected that the radioactivity would make the cancer-cell killing activity even more efficient than using antibodies alone. But radioimmunotherapy is still experimental. Before it’s approved for general use, the treatment must be tested in clinical trials on real patients, with real cancers.

“These patients are really heroes,” says Goris, professor of radiology. “Many of them have told me they know that the treatment is not perfect, but they are willing to do it for other patients who might benefit in the future from their experience.”

In 1996, both Uyeda and Apel were ready to try radioimmunotherapy. Like Apel, Uyeda had failed several rounds of chemotherapy in the eight years between her diagnosis and her arrival at Stanford. Apel’s last remission had lasted a mere three months.



Viola Uyeda: Since radioimmunotherapy five years ago, cancer has not returned.

The procedure is conceptually intimidating — after all, mention injecting radioactivity into someone and they’re likely to be less than thrilled. Add the fact that radiation safety guidelines at the time required patients to remain isolated in their hospital room for three to five days while the radiation dissipated, and it becomes even less appealing. But, as Apel points out, there were no other options.

“I was actually rather frightened about the whole thing, but I didn’t have anything to lose,” says Apel. “When you know that you are going to die, you will do anything to try to find a cure.”

Fortunately the actual administration of the radioactive antibody is both quick and painless — the therapy, which is administered intravenously into the patient’s arm, takes only about an hour. Goris calculates the appropriate dose of radiation for each patient and decides when the patients are able to leave the hospital. Although both Apel and Uyeda had to remain in isolation for a few days after receiving the antibody, radioimmunotherapy patients in ongoing clinical trials at Stanford can now usually return home the same day, says Goris.

“It was the easiest thing I’ve ever done,” says Apel. “It didn’t make me sick; it didn’t make me lose my hair.” She even felt well enough after the procedure to drive back home to Kansas City within two weeks after her treatment.

After the treatment, the waiting began. Every three months, both Uyeda and Apel were examined for signs of cancer. The tests kept coming back negative. Over time, the intervals between check-ups gradually lengthened, and each time they received the same positive news: no sign of lymphoma.

This year marks the fifth since their treatments. Medically speaking, the two women are said to be experiencing an “ongoing, complete response.” But Apel prefers another word.

“They call it in remission, but I call it cured,” she says. “I feel wonderful.”

Knox is also pleased, but a little more cautious with her terminology. “It’s just very exciting,” she says. “Many patients have a better response to radioimmunotherapy than they did to their prior chemotherapy. But we’re very careful not to use the term ‘cured’ given the natural history of the disease.”

Cured or not, Uyeda’s and Apel’s response to the treatment was remarkable. Only a few participants in the clinical trial have maintained remissions for this long, but most patients did benefit significantly from the treatment.

“We’ve treated a number of people and have seen wonderful results, including some ongoing complete responses that have lasted for five or more years,” says Knox. The results of this and other clinical trials of radioimmunotherapy are promising enough for the FDA to consider approving the treatment for non-Hodgkin’s B-cell lymphoma. According to Knox, the official go-ahead may come as soon as this year, opening up a new option for the thousands of non-Hodgkin’s lymphoma patients who are now undergoing round after round of chemotherapy.


Fighting smarter

Even if FDA approval is forthcoming, challenges still remain. Knox and Goris are experimenting with new ways to administer the treatment to make it more effective and even less toxic to the body. They are studying how using just a piece of the antibody that recognizes CD20 will improve delivery to the tumor and reduce the chance that their patients’ immune systems will see the new protein — usually produced by mouse cells — as a foreign invader (see sidebar, page 26). Not only are severe immune responses to the treatment dangerous, but they can also remove the antibody from the blood before it has a chance to attach to the cancer cells. Small bits of proteins can also infiltrate tumors more easily and are more quickly excreted than the whole antibody. Currently Knox and other Stanford physicians are studying radioimmunotherapy of solid tumors, such as colon, sarcoma and pancreatic cancers (see sidebar, page 28).

“I’m very happy with the way the treatment works,” says Goris. “The patients really like it. But I’m not satisfied. I want it to work better and last longer.”

But for Apel, her remission has allowed her to enjoy thousands of precious moments she would otherwise have missed: Not only did she see all three of her children graduate from high school, she’ll be there to cheer when her son receives his doctorate. She’s played with her grandchildren and — three days after the interview for this article — she was climbing on a plane bound for New Zealand for her daughter’s wedding.

“I can’t say loudly or long enough how pleased I am,” says Apel. “I don’t have a moment’s doubt about the fact that the treatment saved my life.”



Fighting Lymphoma: Lab manager John French, professor Michael Goris and nurse Kyoko Hattori visit a patient.

SM

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Copyright © 2001, Stanford University School of Medicine. All rights reserved.