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Radiolabeled Monoclonal Antibody Therapy for Non-Hodgkin's Lymphoma
A promising form of treatment for non-Hodgkin's lymphoma is being studied by Mark S. Kaminski, M.D., and his colleagues at the University of Michigan Comprehensive Cancer Center and sites around the United States. The treatment involves the use of radiolabeled monoclonal antibodies that home to tumor cells.
In contrast to standard chemotherapy, which can have serious side effects, patients participating in clinical trials have had few side effects. In a Phase I study, dramatic tumor remissions have been seen in 70 percent of patients who had undergone prior chemotherapy and had either relapsed or were no longer responding to chemotherapy. In a Phase II study of patients with low-grade lymphoma who have never received any other treatment, 100 percent of patients have had tumor remissions and 70 percent of the time these are complete remissions.
A Phase III randomized controlled study is currently underway at nine institutions.
A report in the Aug. 12 issue of The New England Journal of Medicine details the findings of a team of University of Michigan Medical Center researchers using a new treatment called radioimmunotherapy or RIT. This treatment involves the injection of cancer-seeking and cancer-destroying radioactive monoclonal antibodies into patients with B-cell lymphoma, the most common form of non-Hodgkin's lymphoma. These researchers found that the treatment caused tumors to greatly shrink in size in 70 percent of the patients in their clinical trial and to completely disappear in 50 percent. Remarkably, patients experienced minimal or no side effects from treatment.
"I believe we have made a breakthrough in the logjam we've been encountering for the last two decades in the treatment of this disease," said Mark Kaminski, M.D., associate professor of internal medicine, leader of the Michigan team and director of the Lymphoma/Leukemia Program at the University of Michigan Comprehensive Cancer Center.
This year alone, some 40,000 new cases of non-Hodgkin's lymphoma, or cancer of the lymph system, will be diagnosed in the United States and 20,000 people will die of the disease. More than 80 percent of these cases are B-cell lymphoma in which growing tumors are composed of B-cells (specific types of lymph system cells) that have become malignant. Current treatments include chemotherapy, radiation therapy, and more recently, bone marrow transplantation.However, these treatments are effective in only about half of all cases and can result in severe side effects.
"Since attempts to improve these results by modifying these more standard forms of treatment have largely been unsuccessful, we concluded that we should explore completely different approaches," Kaminski said.
This is precisely what Kaminski and his team set out to do in developing a research program to study the RIT approach. They realized that radiation is one of the single most effective treatment agents in the battle against lymphoma. Unlike many other kinds of cancer cells, lymphoma cells are highly sensitive to radiation. The challenge was to develop a way to get the radiation to all the malignant cells hiding throughout the body without damaging healthy tissues.
The resulting treatment, which is currently being tested in a Phase I clinical trial funded by the National Institutes of Health and the National Cancer Institute, uses monoclonal antibodies armed with radioisotopes to act as guided missiles, homing in on the cancer cells and destroying them. These special antibodies were designed to bind to a protein on the surface of B-cells, which is not found on any other types of cells.
When injected into the bloodstream, these antibodies travel throughout the body and whenever they come in contact with malignant B-cells, they stick to them and not healthy cells. Because these antibodies are armed with radioisotopes, the target lymphoma cells receive a lethal dose of radiation and normal tissues are spared. In addition, once the antibodies have bound to their target, they can also stimulate the immune system to destroy the lymphoma cells. "In effect," says Kaminski, "the malignant cells are subjected to a 'double-whammy.' "
Kaminski and his colleague, Richard L. Wahl, M.D., professor of internal medicine and radiology, division of nuclear medicine, are administering radioactive antibodies to patients who have already failed standard treatment through a single, two-hour intravenous infusion. According to Kaminski, tumors can shrink and completely disappear within days of the injection. And because the radioactive antibodies are targeted to only the malignant cells, patients experience minimal or no side effects. So far in this 18-month-old trial, he says, some patients still remain free of disease, or in complete remission, a year after treatment.
Researchers have been excited in recent years by the potential of radioimmunotherapy in cancer treatment, but until now the results have not lived up to expectations.
"We and other groups have performed prior trials of RIT, and the results were promising but not striking," said Kaminski. "One problem was that the antibodies previously used didn't target well. Also, the actual target on the cell may not have been the right one."
"Critical to the success of this treatment was our identification of the best target (or antigen) on the surface of the tumor cells. We had to find the antibody that could bind to it as well as activate the immune system in the proper way, and tag that antibody with a radioisotope effective in cell killing. This took several years of basic laboratory research."
The antibody used in the current study is called anti-B1, and the radioisotope used is iodine-131. Coulter Corp. of Miami, Florida is producing anti-B1. Currently, Kaminski and his team are experimenting with the amount of radiation attached to the anti-B1 antibody to determine the optimum dosage.
Kaminski views this as one of the most promising developments in the treatment of this disease in many years.
June 1996: Radioactive Antibodies On Seek-And-Destroy Mission
Against Often Incurable Blood Cancer
The therapy caused tumors to greatly shrink or disappear in 79 percent of the 28 patients treated, with minimal or no side effects. The treatment involves injecting into the bloodstream monoclonal antibodies armed with radioactive iodine to zero-in on cancer cells and destroy them.
"For patients with low-grade lymphoma, the results appeared to be particularly promising," said the study's lead author, Mark S. Kaminski, M.D., associate professor of internal medicine. Low-grade lymphoma is a slow-growing but incurable form of the disease that accounts for about 40 percent of newly diagnosed B-cell lymphoma cases. In the study funded by the National Institutes of Health, all 13 patients with low-grade lymphoma responded to the treatment and 10 achieved a complete remission (no evidence of cancer).
The monoclonal antibody used in this study, known as anti-B1, is produced by Coulter Pharmaceutical of Palo Alto, Calif. It attaches to a protein found only on the surface of B-cells, a type of white blood cell that produces disease-fighting antibodies. The targeted tumor cells receive a greater accumulation of lethal radiation while normal tissue is spared. Once bound to the cell, the antibodies also stimulate the immune system to kill any remaining cancer.
Of the 28 patients treated with anti-B1, 50 percent had a complete remission. Six patients continue to be cancer free 16 to 31 months after treatment. "The findings are especially encouraging because all of these patients had failed chemotherapy, a traditional first-line treatment for lymphoma," said Kaminski, who also directs the U-M Cancer Center's Lymphoma/Leukemia Program. "Many of these patients had run out of options because they were no longer responding to chemotherapy."
Kaminski and his co-investigator, Richard L. Wahl, M.D., professor of internal medicine and of radiology, determined the optimal dose of radiation by first injecting the antibody with only a small amount of radioactive iodine attached. This test dose allowed researchers to use individualized information to develop an appropriate therapeutic dose for each patient.
According to Kaminski, the treatment consists of two one-hour injections given about one week apart - first a test dose and then a therapeutic dose. The second injection requires patients to spend only one weekend in the hospital. "This treatment is very attractive to patients because it is simple and quick, in contrast to chemotherapy which typically requires multiple visits over several months. This also has the potential to be a substantially more cost-effective treatment," Kaminski said.
Non-Hodgkin's lymphoma, a form of cancer that affects the blood and lymph tissues, typically strikes in early middle age and often resists standard therapies. It is estimated that nearly 53,000 Americans will be diagnosed this year with non-Hodgkin's lymphoma and nearly half will die of the disease. More than 80 percent of these cases involve malignant B-cells.
Multicenter trials are currently underway to confirm the U-M findings. The researchers and Coulter Pharmaceutical are working with the U.S. Food and Drug Administration to help bring the therapy to market. Kaminski and Wahl also are beginning to study radioimmunotherapy in patients with low-grade lymphoma who previously have not been treated with chemotherapy. "We have every reason to believe the therapy will be even more effective as a first-line treatment, before a patient is exposed to toxic effects of other therapies," Kaminski said.
May 1997: Radioactive Antibodies Show Promise
as First-Line Treatment for Non-Hodgkin's Lymphoma
Mark S. Kaminski, M.D., today reported preliminary clinical data on a radioactive antibody that is being evaluated as a first-line therapy for low-grade non-Hodgkin's lymphoma, a blood-borne cancer. Kaminski, who is an associate professor of internal medicine at the U-M and the principal investigator for the trial, presented the data at the American Society of Clinical Oncology meeting in Denver.
Preliminary data shows that all patients in Kaminski's study responded to the therapy and experienced a greater than 50 percent shrinkage of their tumors. These results were generated from 17 patients recently diagnosed with advanced, low-grade B-cell lymphoma. None of these patients had previously received treatment.
Following a single radioactive antibody infusion, all 17 patients experienced a reduction in tumor mass of more than 50 percent. Seven had complete remissions with no detectable cancer cells, and nine were classified as "partial responses" with ongoing tumor shrinkage. One patient relapsed. The study eventually will be expanded to 60 patients.
"These preliminary results are encouraging and demonstrate the promise of this therapy to be more effective and less toxic than traditional chemotherapy regimens," Kaminski said. "The therapy does not appear to cause many of the side effects typically associated with chemotherapy. We look forward to completing the study and assessing the long-term benefits of this antibody therapy." Side effects of the antibody therapy were minimal and included a flu-like syndrome which seven participants experienced for a day or two.
In earlier studies, Kaminski achieved encouraging results in patients who had undergone conventional treatments and failed to respond. The latest trial suggests the antibodies also may be effective working alone as a front-end treatment in newly diagnosed cancer patients.
The antibody treatment consists of two one-hour infusions administered about a week apart -- first a test dose and then a therapeutic dose. Conventional chemotherapy, on the other hand, requires treatment to be given repeatedly over several months.
In Kaminski's study, antibodies armed with radioisotope iodine-131 are injected into the bloodstream and act as guided missiles, homing in on the cancer cells and destroying them while steering clear of healthy cells.
Non-Hodgkin's lymphoma typically strikes in early middle age and often resists standard therapies. There are about 54,000 cases diagnosed each year in the United States, and more than 80 percent involve malignant B cells.
Approximately one-third of the total cases is diagnosed as low-grade B-cell lymphoma, which is the type afflicting Kaminski's study subjects. The antibody used in the study goes by the trade name of Bexxar and belongs to Coulter Pharmaceutical of Palo Alto, Calif.
May 1998: Bexxar Demonstrates Promise as First-Line Therapy for Non-Hodgkin's Lymphoma
At the American Society of Clinical Oncology meeting in Los Angeles, University of Michigan researcher Mark S. Kaminski, M.D., reported Phase II data on a radiolabeled monoclonal antibody called Bexxar, which is being investigated as a treatment for low-grade and transformed low-grade non-Hodgkin's lymphoma (NHL), an incurable form of lymphoma. The preliminary results, from 32 patients of a planned 60-patient trial, which is now closed at the University of Michigan, revealed that 100 percent of newly-diagnosed patients with advanced low-grade NHL responded to Bexxar, with 71 percent (of 24 patients who had adequate follow-up for at least six months) experiencing complete remission (or complete disappearance) of their disease.
Additionally, no evidence of NHL was detected at molecular levels using polymerase chain reaction (PCR) analysis in nine patients. The complete remissions were determined by physical exams, CT scans and, if appropriate, bone marrow biopsy. At the time of the presentation, complete remissions were still going on in 16 patients with the longest remission ongoing at 18.5 months and the median not yet reached. Eight of 32 patients had relapsed. Bexxar was well tolerated with patients experiencing moderate, reversible low blood counts. A minority of patients experienced a flu-like syndrome consisting of fever, headache and muscle and joint pains. Dr. Kaminski also reported that with a single therapeutic dose of Bexxar, patients also were able to achieve molecular remission -- a remission state that is believed to coincide with prolonged, durable responses. Polymerase chain reaction (PCR) technology was used to detect molecular levels of NHL in 14 patients whose bone marrow tested positive for the BCL-2 translocation at baseline, a prevalent molecular marker for low-grade NHL. In this subset of patients, 10 of the 14 patients (71 percent) treated with Bexxar achieved a complete remission and nine achieved molecular remissions (no detectable signs of disease in bone marrow as determined by PCR negative results), PCR analyses were conducted at baseline and multiple time points following Bexxar therapy, including periods following B-cell recovery. Additionally, conversion from PCR positivity at baseline to PCR negativity post-therapy was confirmed by a masked, independent analysis of samples by investigators at Dana Farber Cancer Institute in Boston. "Bexxar continues to demonstrate promise as a stand-alone, first-line agent for the treatment of low-grade NHL," said Dr. Kaminski. "These most recent PCR data are particularly encouraging as molecular remissions supported by PCR negativity in bone marrow is a rarity in patients treated with conventional chemotherapy. Although preliminary, these results suggest that newly-diagnosed patients treated with Bexxar may enjoy longer disease-free remissions than with chemotherapy, but further follow-up and additional patients will be required to confirm this hypothesis."
Grants from Coulter Pharmaceutical, Inc. and the National Cancer Institute support this study.
Bexxar is administered in a regimen that consists of a dosimetric dose followed approximately one week later by a therapeutic dose. The therapy is an antibody conjugated to radiolabeled iodine. The therapy attaches to the CD20 antigen found only on the surface of B-cells, both non-Hodgkin's lymphoma B-cells and some normal B-cells. It is believed that through this targeted approach, the tumor cells receive a greater concentration of the therapeutic radiation from Bexxar relative to normal tissues.
Coulter Pharmaceutical, Inc. can be reached at