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Researchers Focus on Bioimmunotherapy for Treatment of Non-Hodgkin’s Lymphomasby Beth Notzon The sheer number of non-Hodgkin’s lymphomas—about 30 in all—has always presented a complex challenge to researchers. Whether they are indolent and grow slowly, like follicular lymphoma, or are aggressive, fast-growing tumors such as Burkitt’s lymphoma, all are serious cancers. Now the incidence of non-Hodgkin’s lymphoma, already the fifth most common cancer in the United States, is on the rise and so is the pressure on researchers to develop better treatments and more sensitive diagnostic techniques for this diverse group of tumors.
In part because lymphomas are derived from lymphocytes, which are part of the immune system, these tumors are particularly good candidates for treatment with bioimmunotherapy, said Fernando Cabanillas, M.D., chairman of the Department of Lymphoma and Myeloma at The University of Texas M. D. Anderson Cancer Center. Rituximab, one of the first success stories in bioimmunotherapy for cancer, is being studied further in clinical trials of patients with indolent B-cell lymphomas, which constitute 40% of the cases of non-Hodgkin’s lymphoma. Despite the usually slow growth of these tumors, the long-term mortality rate is high because the tumors often become resistant to current standard treatments. Peter McLaughlin, M.D., a professor in the Department of Lymphoma and Myeloma who has headed up much of the research on rituximab at M. D. Anderson, explained that rituximab is an unconjugated anti-CD20 monoclonal antibody that recognizes and disrupts the activity of CD20, a transmembrane protein found normally on B cells but also expressed on most B-cell lymphomas. Antibodies against CD20 have proven to be effective targeted therapies, both in an unconjugated form (rituximab) and when linked to radioisotopes to deliver targeted radiotherapy (Zevalin). The role of CD20 in normal B cell biology and in the development and progression of B-cell lymphomas remains incompletely understood and Is the focus of much current research. Researchers in the Department of Lymphoma and Myeloma at M. D. Anderson led a large multicenter clinical trial of rituximab that concluded in 1996. In this study, in which rituximab was used alone, a response rate as high as 69% was seen in certain groups of patients. A particular advantage of rituximab is that it seldom causes serious side effects. This is especially good news for elderly patients with comorbid conditions and for patients who have had bone marrow transplants. Now rituximab is being studied in combination with standard chemotherapy regimens and has shown a synergistic effect with certain chemotherapeutic agents. A new clinical trial is investigating the combination of rituximab and epratuzamab, an anti-CD22 monoclonal antibody, without chemotherapy.
Zevalin, another anti-CD20 antibody, is being studied for use in radio-immunotherapy. In this treatment, the antibody attaches to CD20 on the cancer cell and delivers a radioisotope, yttrium 90, which has a long-range effect, killing tumor cells up to a few millimeters away from the target tumor cell. This treatment is efficacious when a large amount of the radioisotope is delivered by the antibody to the tumor, said Franklin C. Wong, M.D., Ph.D., J.D., an associate professor in the departments of Nuclear Medicine and Neuro-Oncology. Dr. Cabanillas pointed out that a particularly intriguing mechanism of this therapy is that the radioisotope can destroy not only the tumor cells with CD20 but also, through a “cross fire” effect, nearby tumor cells that do not have the antigen. Zevalin is approved for use in patients with recurrent indolent B-cell lymphoma, including those with disease resistant to rituximab. Clinical studies of the therapeutic effects of radio-iodinated antibody against CD20 in patients with lymphoma are also under way at M. D. Anderson and other institutions. Another cell-surface protein that holds promise as a target for the treatment of lymphomas is CD26, which is the focus of preclinical research being conducted by Nam Hoang Dang, M.D., Ph.D., an assistant professor in the Department of Lymphoma and Myeloma. This work extends previous findings by Dr. Dang in collaboration with Chikao Morimoto, M.D., a research professor in the department, that demonstrate a key role for CD26 in normal T lymphocyte function. CD26 is involved in the development of T-cell lymphoma, a very aggressive type of non-Hodgkin’s lymphoma. Most T-cell lymphomas are so aggressive, in fact, that patients with the disease are expected to live only a few months to a year with current treatment. Dr. Dang explained that most patients with T-cell lymphoma have disease in the bone marrow, lymph nodes, and other sites at the time of diagnosis. Adding to this bleak picture is the fact that T-cell lymphomas are very refractory to current treatments. Thus, a critical need exists for better treatments for this type of lymphoma. In laboratory studies, early indications are that the antibody to CD26 inhibits the growth of T-cell lymphomas, at least in mice. Like rituximab, the antibody to CD26 may augment the effectiveness of other therapies, either by making cells more sensitive to chemotherapy or by reducing the number of cancer cells the chemotherapy has to destroy. CD26 itself may also sensitize lymphomas to certain types of chemotherapy by affecting certain cellular processes in the tumor cells. Additional studies are being performed to translate these laboratory findings to animal models, with potential implications for the treatment of patients with T-cell lymphomas as well as other lymphomas. Taking advantage of what is known about CD26 biology, Dr. Dang has initiated a clinical trial evaluating the effect of chemotherapy on CD26 expression in tumor cells and in normal T lymphocytes. Researchers at M. D. Anderson have also been developing a quantitative technique that is sensitive enough to determine whether a patient with follicular lymphoma is in molecular remission—that is, if the number of tumor cells has become so low that the cancer can no longer be detected. Andreas H. Sarris, M.D., Ph.D., a former member of the Department of Lymphoma and Myeloma, and Yunfang Jiang, M.D., Ph.D., a research scientist in the department, began using quantitative polymerase chain reaction to test for molecular remission, and the technique is now the focus of research being done by Andre Goy, M.D., an assistant professor in the department. Dr. Cabanillas explained that the test can detect one abnormal cell out of 100,000 normal cells on the basis of a certain genetic abnormality. The particular strength of this test resides in its potential ability to help clinicians decide whether to increase a patient’s dosage or change the treatment—or whether to consider the patient potentially cured. “The data show that, without a doubt, patients who achieve a molecular remission have a much longer period of remission. If they have minimal residual disease, however, they will have a relapse within two years,” said Dr. Cabanillas. At an even more basic scientific level, researchers are looking for the causes of non-Hodgkin’s lymphoma and trying to identify the molecular mechanisms involved. In one such effort, Felipe Samaniego, M.D., an assistant professor in the department, is identifying how human herpesvirus 8 may cause primary effusion lymphoma. (For more details, please see DiaLog on page 8.) Although a viral etiology for non-Hodgkin’s lymphoma remains more suspected than proven, this may be the first real evidence that a virus can cause lymphoma. Other molecular research is being conducted in Dr. Goy’s laboratory, where the molecular profile of diffuse large cell lymphoma tumors is being studied in vivo to define a subset of genes that could help predict the tumor’s response to chemotherapy. “This is a very exciting project that is part of our broader efforts to define the genes important in the progression and prognosis of lymphomas,” Dr. Goy said. A discussion of bioimmunotherapy would not be complete without a look at a vaccine being tested in patients with indolent non-Hodgkin’s lymphoma. A particular problem with advanced indolent lymphoma, as Dr. Cabanillas explained, is that “although the tumor is very slow growing, the patients’ chances of cure are very low.” The most likely reason for the ineffectiveness of current standard treatments for this type of lymphoma is that they preferentially target rapidly cycling cell populations. Because cells in the slow-growing types of non-Hodgkin’s lymphoma divide slowly, the chemotherapy simply cannot find its target. A tumor vaccine being tested by Anas Younes, M.D., an associate professor in the Department of Lymphoma and Myeloma, may overcome some of the problems seen with standard therapies. The vaccine, which is called HSPPC-96, is made using a cancerous lymph node removed from the patient being treated. Dr. Younes explained that of the nine patients enrolled so far in a phase II trial of HSPPC-96, none has shown any major side effects, and two have shown a response. Generally, tumor vaccines differ from vaccines for such diseases as polio and smallpox in that, first of all, they are being used to treat, not to prevent, the cancer, and second, they are made specifically for a particular patient. Dr. Younes explained that this is necessary because, although different patients can have the same type of lymphoma, one patient might have a tumor that makes five antigens, whereas another patient’s tumor might produce 200 antigens. Therefore, a vaccine that works in the first patient would not work in the second patient. Dr. Younes noted that if results from the phase II trial are encouraging, the vaccine will be tested in patients with indolent lymphomas who are in complete remission to see if it can prolong the duration of remission or increase the cure rate. More than 25 years ago, members of the Department of Lymphoma and Myeloma conducted the work that led to the landmark development of the CHOP regimen (cyclophosphamide, hydroxydaunomycin, Oncovin [vin-cristine], and prednisone) for non-Hodgkin’s disease. More recently, they developed the now-standard and very effective FND regimen (fludarabine, Novantrone [mitoxantrone], and dexamethasone), as well as a number of other regimens used as salvage therapy. This legacy of innovation lives on as researchers cast a wide net in their search for ways to improve the prospects of patients with lymphoma. For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other articles in OncoLog, April 2002 issue:
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