Radiology brings biotechnology into the picture to combat cancer
By Joyce Ward, CNMT, RT(N)
Lymphoma is a term used to describe a group of malignant disorders that originate in lymphocytes, a type of white blood cell. According to the Leukemia Society of America, approximately 52,900 Americans are diagnosed with non-Hodgkin’s lymphoma every year. In many cases, by the time a patient is diagnosed with lymphoma, the malignant cells have spread throughout the body.
The widespread nature of lymphoma limits the usefulness of conventional surgery or radiation therapy in treating the disease. Most treatments for lymphoma use chemotherapy agents that circulate throughout the body to destroy distant sites of disease. The problem with chemotherapy is it is not specific enough to target lymphoma cells only without damaging other cells in the body. This lack of specificity limits the amount of chemotherapy that can be given safely.
Scientists looking for alternative treatments to chemotherapy are turning to treatments involving monoclonal antibodies (MAbs). Clinical trials are being conducted at a number of sites to study the effectiveness of treatments for non-Hodgkin’s lymphoma that include MAbs, which target specific cells and stimulate the immune system to attack them, and radiolabeled MAbs, which bring radiation therapy and an immune response to the lymphoma sites. The advantage of radiolabeled MAbs is the radiation destroys surrounding cells that may not have been bound by the antibody.
“Lymphoma cells are very sensitive to radiation, much more than other tumor cells,” said Mark S. Kaminski, MD, associate professor of internal medicine and director of the Leukemia, Lymphoma Pro-gram at the Cancer Center of the University of Michigan in Ann Arbor. “So if you combine the antibody with radiation, you have a sort of guided missile approach where the antibody will seek out the lymphoma and, as it accumulates in the tumor, the radiation dose will be concentrated in the tumor; the rest of the body will be relatively spared. This is a more targeted therapy than traditional treatments such as chemotherapy. If you have an immune system that is inefficient and unable to react properly to the antibody, the radiation compensates for this by killing the cell it is attached to and also neighboring cells.”
Lymphoma cells are an excellent target for immunotherapy with radiolabeled and unlabeled MAbs because they have specific antigens that are not present on other cells. “Most non-Hodgkins lymphomas aremalignancies of the B lymphocyte that can be targeted with an anti CD-20 MAb. The CD20 antigen is present on over 95 percent of the B-cell lymphomas,” said Christine A. White, MD, senior director of oncology and hematology at IDEC Pharmaceuticals Corp. in San Diego, Calif.
“The CD-20 antigen is an excellent target for immuno-therapy as the antigen is not shed into the blood, internalized, or modulated by the cell. IDEC’s Anti CD20 Mabs, Rituxan™ and IDEC-Y2B8 specifically bind to lymphoma cells in the lymph nodes and the blood. Although the antibody also attaches to some normal B cells, it does bind other cells in the body, as CD20 is only present on a subset of B cells. It is not present on stem cells of the bone marrow, nor the mature B cells that are secreting antibody.”
When radiolabeling MAbs, it is important for the researchers to chose a suitable radioisotope. “In radiolabeling the antibody, researchers choose an isotope with a physical property that will not only to kill the malignant cell that it is attached to but will be able to reach a little deeper into the tumor mass,” Dr. White explained. Penetrating radiation can obviate the problem of limited access in a bulky or poorly vascularized tumor lesion.
Among radioisotopes under consideration, researchers are using iodine-131 (I-131) and yttrium-90 in clinical trials of radiolabled MAbs. For their studies, researchers at the University of Michigan are using I-131, which emits gamma rays and beta rays. Along with being more available and less expensive than other beta emitters, the gamma ray emission allows clinicians to image the patient with a gamma camera.
“We image first with a very small dose of I-131-labeled anti-B1 (anti-CD-20), manufactured by Coulter Pharmaceuticals in Palo Alto, Calif.,” Dr. Kaminski said. “This gives information on the deposition of the antibody and the clearance over an intervening time. We can then use the information to scale up and adjust the dose to the individual patient. We have developed a simple method of calculation which scales the dose to give 75 rads to the whole body with the tumors getting from 500 to 2000 centigrays (rads).”
In order to prevent the patient’s thyroid from taking up the radioiodine, the clinician administers a solution of potassium iodide prior to and during treatment to saturate the gland. This may not totally block radioiodine uptake by the thyroid during therapy. Some otherwise asymptomatic patients have shown an increase in thyroid-stimulating hormone, indicating thyroid function was slightly suppressed because of radiation exposure, Dr. Kaminski noted.
The University of Michigan researchers are performing trials of the MAb I-131 anti-BI. “We are conducting a number of multi-center trials on patients who have relapsed after chemotherapy; one study is in very refractory patients,” Dr. Kaminski said. “In another study on less refractory patients, we are doing a randomized study between the unlabeled antibody and the hot (radiolabeled) antibody to see what the incremental action of the radiolabeled antibody is.” Patients who do not respond to the unlabeled MAb are given a dose of the radiolabeled antibody after the study is completed.
In addition, researchers at the hospital are conducting a study on patients who have never been treated with chemotherapy or any other therapy; for advanced, low-grade lymphoma. “We have been seeing encouraging results in our trials,” Dr. Kaminski said. “Over 60 percent of patients who were refractory to their last chemo-therapy treatments responded to this treatment. Also, the number of complete responses has been quite high, with some remissions lasting out to 5 years.”
Another advantage to using radiolabeled MAbs is patients rarely have side effects similar to those experienced by pa-tients undergoing chemo-therapy, Dr. Kaminski indicated. “Patients do not lose their hair; they rarely have nausea, fever or body aches, and then those only last for a few days,” he explained. “There is some moderate blood count suppression about 4 to 6 weeks later. The patients can usually be done as outpatients.”
At IDEC Pharmaceuticals, researchers have chosen to use the beta-emitting isotope yttrium-90 with their MAb therapy agent called IDEC Y2B8. “We feel that yttrium-90 is an ideal radiotherapy agent because it securely attaches to the antibody, has stable daughter products and does not have to be internalized for cell killing,” Dr. White said. “Yttrium-90 delivers a high beta emission to the tumor site without any gamma radiation that might effect distant parts of the body. It has an excellent pathlength for a beta emitter, 5 to 10 milllimeters, allowing radiation to penetrate tumor masses yet have no distant effects on other persons standing nearby. For this reason, the therapy can be given on an outpatient basis.”
Because the beta emission of IDEC-Y2B8 cannot be imaged with a gamma camera, the patients in the IDEC trials come in one week before the therapy for an injection of MAbs labeled with a small amount of gamma emitting indium-111. This allows the researchers to determine if the isotope is accumulating in the tumor and if there is any excessive uptake in a healthy organ.
“We have conservatively chosen to restrict our patient population to those with less than 25 percent bone marrow involvement; but it is very rare for a patient to fail this screening,” Dr. White emphasized. “We have chosen to work with a nonmyeloablative approach to therapy (in myeloablation all bone marrow cells are destroyed by the therapy) to avoid the safety risks and economic burdens of stem cell rescue and transplantation. IDEC-Y2B8 therapy is one that any good nuclear medicine or radiation oncology department can handle.”
The injections of the indium-and yttrium-labeled MAbs are performed in conjunction with injections of IDEC’s unlabeled MAb called Rituxan, the chimeric form of the anti-CD-20 2B8, recently approved by the Food and Drug Administration for use in treating relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. (The radiolabeled IDEC Y2B8 uses a murine antibody similar to Rituxan.)
“In an abstract published in Cancer Biotherapy and Radio-pharmaceuticals (Vol. 13, No. 1, Feb. 1998) we presented interm analysis data that demonstrate an 82 percent response rate in patients with relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma who were treated with 0.4 mCi/kg of the Y2B8,” Dr. White said. “We also have treated a smaller number of intermediate-grade lymphoma patients, and other patients with multiple dose regimes.” Gregory Wiseman, MD, consultant in nuclear medicine at the Mayo Clinic, Rochester, Minn., who is involved in the current phase III trials of Y2B8, will present information on these studies at the 45th Annual Meeting of the Society of Nuclear Medicine this June in Toronto.
Joyce Ward is the technical editor at ADVANCE.