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U-M CCC - Michigan Oncology Journal Fall 2000

Antibody Therapy for Non-Hodgkin's Lymphoma

New forms of treatment that are different from traditional chemotherapy are adding more options and creating a potentially brighter future for patients with non-Hodgkin's lymphoma (NHL). Among the most promising of these new approaches is treatment with monoclonal antibodies that specifically bind to antigens expressed by tumor cells.

Although clinical trials using antibodies have been conducted for a variety of cancers, the largest experience and the most successful applications of this treatment have been in patients with NHL. The most promising results so far have come from trials using antibodies that bind to an antigen called CD20.

CD20 is a cell membrane phosphoprotein expressed by virtually all B-cell NHLs. It is also found on a subset of normal B-cells but no other tissues of the body. Specifically, it is not found on immature B-cells and mature antibody-secreting plasma cells. This is important because even if a treatment could eliminate all CD20-expressing normal and lymphoma cells in the body, the unaffected immature cells would continue to mature and to reconstitute the missing population. Meanwhile, spared plasma cells would continue to function and maintain immune protection.

The function of the CD20 protein is not known, but antibody binding to this antigen can induce apoptosis. Antibodies bound to CD20 can also activate cellular and complement lysis mechanisms that can result in tumor cell destruction.

In 1998, FDA approval was obtained for the CD20 antibody Rituxan (rituximab) for the treatment of patients with chemotherapy-relapsed or refractory low-grade or follicular NHL --- a disease that is generally responsive to, but incurable with, chemotherapy. In a study of 166 such patients, 48% had tumor regressions and 6% achieved complete remission (1). Tumor responses generally lasted 11 to 12 months.

Rituxan (a chimeric antibody composed of some mouse but mostly human sequences) is given intravenously slowly over several hours in an outpatient setting, once a week for four doses. The side-effect profile of Rituxan is quite different from that of chemotherapy in that there is no hair loss and usually no significant lowering of blood counts, nausea or vomiting. Instead, fever and chills are commonly seen, especially during the first infusion. Subsequent infusions are usually associated with fewer side effects.

Recently, Rituxan has been investigated for treatment of relapsed/refractory intermediate/high-grade or mantle-cell NHL. Response rates have been lower in such patients (about 30%) and of shorter duration compared to those with low-grade NHL (2).

Because the side-effect profiles of Rituxan and chemotherapy do not overlap and because some laboratory data indicates that Rituxan may sensitize lymphoma cells to some chemotherapeutic drugs, there has been interest in combining the two treatments. Results from completed and ongoing trials indicate that they can be safely combined without increasing the toxicity of either treatment (3). Rituxan has been given before chemotherapy, in between chemotherapy cycles, and after. High response rates have been seen, but whether there is truly an added value of combining these treatments awaits the results of ongoing controlled trials com-paring chemotherapy alone versus the combination.

Another successful approach has been to use antibodies as carriers of radioisotopes. In the laboratory, antibodies can be made to be radioactive by chemically attaching radioisotopes. When injected into the bloodstream, they home to tumor sites. Over time, these radioactive antibodies accumulate in the tumor, and tumor cells are constantly bombarded by subatomic particles these antibodies emit. Radioisotopes, such as iodine-131 (I-131), can emit particles that travel through a layer of about 20 to 40 tumor cells. In this way, even if an antibody cannot penetrate into the deep recesses of a tumor, its radiation emissions can still reach these distant tumor cells.

This approach makes good sense for the treatment of lymphoma since lymphoma cells are extraordinarily sensitive to the effects of radiation. Furthermore, these radioactive antibodies can still retain their ability to flag the cells they attach to for immune system destruction.

Several different radioactive antibodies have been tested in NHL. None have yet achieved FDA approval, but Bexxarª is the furthest along in development. Bexxarª is a mouse monoclonal anti-CD20 antibody tagged with the radioisotope I-131. The initial trials and subsequent development of Bexxarª actually began at the University of Michigan in 1990.

Bexxarª is given in a two-stage process. First, a dosimetric dose is given, followed one week later by a therapeutic dose. The dosimetric dose consists of a small amount of antibody that has been lightly labeled with I-131. Three times during the next week, the patient is measured for the amount of radiation in the body. I-131 emits both strong, short-range beta particles and weaker long-range gamma rays. The latter can be detected by a gamma camera. Based on the rate of decline of radiation counts, the amount of I-131 that is tagged to antibody for the therapeutic dose is adjusted for the individual patient. Just prior to both radioactive antibody injections, unlabeled antibody is given over an hour to make the radioactive antibodies penetrate more efficiently to tumor sites. The total infusion time for each session is about 90 minutes. After the therapeutic dose, in most states, the patient is sent home with some simple instructions as to how to minimize the radiation exposure of individuals in the community for approximately one week. In some states, 2 to 3 days of hospitalization are required until an appropriate radiation level is reached. This completes the entire treatment, and no further cycles of treatment are given.

Initial trials at the University of Michigan demonstrated that Bexxarª was more effective for low-grade NHL than for intermediate-grade NHL (4,5). Confirmatory multicenter trials in chemotherapy-relapsed/refractory low-grade NHL have shown overall response rates in the 70% range and complete response rates around 30% (6,7). Complete remission durations have been durable (median about 30 months, ranging up to 7 years). Recently, a clinical trial was conducted at U-M in 76 patients with low-grade NHL who had not had any previous treatment. An overall response rate of 97% and a complete response rate of 76% were seen (8).

The principal toxicity is myelosuppression. This is usually moderate and rarely results in a need for medical intervention. About 10% of patients who had previous chemotherapy develop neutralizing antibodies against the mouse antibody. This may prevent these patients from receiving Bexxar again.

Zevalinª is another radioactive anti-CD20 antibody. It is tagged with ytrrium-90 (Y-90), which differs from I-131 in that it only emits strong short-range beta particles and no gamma rays. This allows all patients to be treated as outpatients because all the radiation is confined inside the body. This advantage is counterbalanced by an inability to individualize doses for each patient. Nevertheless, preliminary treatment results are encouraging (9).

In summary, antibodies, either in an unmodified form or in a radioisotope-tagged form, are making a strong mark on the treatment of NHL. The challenge for the future is to learn how best to incorporate these new options into the care of NHL. Therefore, patients should be encouraged to participate in clinical trials so important questions can be answered as quickly as possible.

References

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