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Wilmot Team Eyes Tactics to Combat Lymphoma, Predict Survival

Tuesday, November 23, 2004

Non-Hodgkin’s lymphoma is one of the most treatable forms of cancer because research over the last decade brought new, targeted therapies to improve survival rates.  Scientists at the James P. Wilmot Cancer Center at the University of Rochester Medical Center are building upon that momentum -- studying new therapies to fight these cancer cells and helping create a model for doctors to predict which people will survive the disease.

Two papers published this week highlight some of the progress made to treat one form of NHL—follicular lymphoma—done in part by UR scientists and hematologists. 

The Wilmot Cancer Center has established one of the largest lymphoma teams in the Northeast with five physicians specializing in treatment and clinical and basic science research. The team offers patients access to dozens of clinical trials and people are traveling from throughout the nation for their expertise.

Predicting Survival

Richard I. Fisher, M.D., director of the Wilmot Cancer Center, helped develop a new model that predicts the survival of follicular lymphoma patients based on the molecular characteristics of their tumors at diagnosis. 

The model is based on two sets of genes—called survival-associated signatures—whose activity was found to be associated with good or poor prognosis for patients with this type of cancer.  The results, published in the Nov.18, issue of the New England Journal of Medicine, suggest that immune cells infiltrating follicular lymphoma tumors have an important impact on survival—both signatures came from such immune cells.

About a half-million Americans have some kind of lymphoma, which affects the body’s lymphatic system.  One of the first symptoms of the disease, which is about twice as common as it was 30 years ago, is often a swollen lymph node, though weight loss and fevers are also common.

The progression rate of follicular lymphoma, one of the most common form of non-Hodgkin’s lymphoma, varies widely. 

“Some people see slow growth of the disease over years, while others face an aggressive lymphoma that leads to an early death,” says Fisher, chair of the lymphoma committee for the Southwest Oncology Group, a national clinical research cooperative. “Understanding the molecular causes of such differences in survival could provide a more accurate method to determine patient risk, which could be used to guide treatment and may suggest new therapeutic approaches.”

The two-signature model allowed the lymphoma researchers to divide patients into four groups with varying average survival rates -- 3.9, 10.8, 11.1, and 13.6 years.  Treatments can be adjusted for patients; prognosis,” Fisher said. 

“Some patients would benefit from knowing that they may not need treatment for quite some time. On the other hand, those patients in the group with the lowest survival rate should be considered for newer treatments and clinical trials.”

To create their model, Fisher and a research team led by Louis M. Staudt, M.D., Ph.D., of National Cancer Institute’s Center for Cancer Research, used follicular lymphoma biopsies taken from 191 untreated patients.  The biopsies were taken between 1974 and 2001 and came from the NCI-sponsored Lymphoma/Leukemia Molecular Profiling Project.  Following their biopsies, all patients received standard treatments.

The scientists examined their subsequent medical records to determine survival.  Biopsies were divided into two groups balanced for survival and institution: 95 went into a group used to uncover gene expression patterns associated with survival; the other 95 were used to test the predictive power of these patterns.

The team first used a DNA microarray to determine which genes were active in the first group of 95 tumor biopsies, and at what levels.  They then determined which of these genes were statistically associated with survival.  They called those associated with long survival “good prognosis genes” and those associated with short survival “poor prognosis genes.”

Next, the researchers identified subsets of both kinds of genes that tended to be expressed together.  These they named “survival-associated signatures.” 

Two signatures—one which indicated poor prognosis, the other good—had strong synergy and together predicted survival better than any other model tested. 

Unexpectedly, both came from nonmalignant immune cells infiltrating the tumors.  The good prognosis signature genes reflect a mixture of immune cells that is dominated by T cells.  T cells react to specific threats to the body’s health. In contrast, the poor prognosis signature genes reflect a different group of immune cells dominated by macrophages and/or dendritic cells—which react to nonspecific threats—rather than T cells.

New Treatments

Scientists are testing new ways to boost the body’s immune system to fight follicular lymphoma. Many people with the disease have benefited greatly from a highly targeted cancer treatment known as rituximab. Even so, about half of patients don’t respond to the drug, and physicians are looking for ways to improve treatment.

In a paper published in the on-line edition of the journal Blood, doctors at the Wilmot Cancer Center and the Dana-Farber Cancer Institute in Boston discuss results of an initial study with a new compound that activates the body’s immune system. Doctors are hopeful that such activation could help lymphoma patients, particularly since rituximab (brand name Rituxan) relies on the body’s immune system to destroy the cells it has tagged for destruction.

The work is an important step toward improvement of treatment for the more than half a million Americans who have some form of lymphoma.

“While the gains with Rituxan have been truly remarkable, enhancing this therapy is an important theme in lymphoma research,” says Jonathan Friedberg, M.D., a lymphoma specialist and assistant professor at the Wilmot Cancer Center. “It may be that Rituxan may not work in certain situations because the immune system isn’t working properly. We’re trying to stimulate the immune system to augment the Rituxan response, while maintaining the highly favorable toxicity profile.”

Rituximab became available to patients in 1997 and revolutionized the way lymphoma is treated. It was the first monoclonal antibody therapy approved for any cancer, a highly targeted treatment that translates into fewer side effects for patients than traditional chemotherapy. Now there are several monoclonal antibodies used for diseases such as breast and colorectal cancer.

Rituximab can be given multiple times over the course of a patient’s lifetime and has helped most patients with follicular lymphoma. But even with its success, about half of patients don’t respond to the drug, and the disease will recur even in patients who do respond.

In an attempt to improve outcomes following rituximab therapy, doctors tested a novel compound made by California-based Dynavax Technologies – the compound is made up of short strands of DNA that mimic bacterial DNA by repeating certain segments of code normally found only in bacteria. “This is the same type of material your body sees when you have a bacterial infection,” Friedberg says.

Doctors combined the compound with rituximab in 20 patients with follicular lymphoma, an incurable disease that generally progresses over eight to 10 years. The team showed that the compound, called 1018 ISS, turns on several immune system genes normally activated by interferon-alpha, a compound doctors now turn to occasionally to fight some cancers. But agents like interferons and interleukins typically carry severe side effects, such as long-term flu-like symptoms, and none has been approved to treat lymphoma.

The new compound is aimed at spurring the immune system while causing fewer side effects. “Patients on this study tolerated therapy extremely well, and in fact the only significant side effect we observed included minimal redness at the injection sites,” says Friedberg.

The exciting results of the initial study, which was done largely at Dana-Farber by Friedberg before he joined the University of Rochester in 2002, have spurred the National Institutes of Health to fund a larger study in patients at Rochester and Dana-Farber. The second study, which will include extensive laboratory work at the Wilmot Cancer Center, is currently enrolling patients and will include about 30 participants.

The study was funded by the National Institutes of Health, the Norman Hirschfield Foundation, Dynavax Technologies, and the Leukemia and Lymphoma Society. The results were first presented at the American Society of Hematology meeting last December.


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