This coverage is supported by an educational grant from

Presented by Gregory A. Wiseman, MD, at the Radioimmunotherapy of Non-Hodgkin's Lymphoma symposium, provided by the Institute of Continuing Healthcare Education, held at the American Society of Hematology 42nd Annual Meeting, December 1, 2000, in San Francisco, California.

Radioimmunotherapy is very appealing for treatment of lymphoma, in that lymphoma cells remain inherently sensitive to radiotherapy even when resistant to chemotherapy. The advantage to radioimmunotherapy is that the cell does not have to be bound by the antibody to receive the cytotoxic radiation. For example, if a radiolabeled antibody binds to one, but not the other, of two lymphoma cells in close proximity, the unbound cell will still receive the radiation similar to the cell that is bound. The advantage, then, is that radioimmunotherapy tries to overcome some of the problems that we have seen with antibody therapy alone. This differs from the treatments that we have now for lymphoma.

With external beam therapy we are radiating a limited area of the body. With chemotherapy, the treatment is a systemic treatment that goes throughout the body, and the therapy depends on the differences in sensitivity from the normal tissue compared to the tumor. With targeted radioimmunotherapy, however, the antibody is actually the carrier for the toxic substance, and delivers the toxic substance to the site of the tumor.

This report focusses mainly on the CD20 antigen, which is expressed only on B-cells. CD20 is important for cell cycle initiation and cell differentiation, and is ideal for targeting due to the fact that it is anchored into the membrane and doesn't shed or internalize. CD20 is also an excellent tumor target in that it is expressed almost exclusively on lymphoma cells. Plasma cells, which make the immunoglobulin, do not generally express this antigen, so they continue to make immunoglobulin to protect from infection. Similarly, pluripotent stem cells do not express CD20, so they continue to make cell precursors. While these cell populations are lowered both with this therapy and with the anti-CD20 monoclonal antibody therapies, they soon replenish and, in most cases, it does not appear that there is an increased risk of infection for the patient.

There are two radioisotopes that are being used today for radioimmunotherapy. The first is yttrium-90, which decays to zirconium-90, and has a half-life of 64 hours. There is essentially no gamma radiation associated with Y-90, making it impossible to image directly.

Iodine-131, the other radioisotope being used in clinical trials at this time, has been available for many years for treating thyroid cancer. It is now being used to attach to an antibody to provide a way of performing radioimmunotherapy. I-131 has a half-life of eight days -- significantly longer than Y-90. It also differs from the Y-90 in that it gives off gamma radiation, which can be imaged with a standard gamma camera.

The issue of radioactive decay is important because it is the mechanism by which the antibody is visualized when it is a gamma ray, and is the means by which the therapeutic potential of the isotope is realized through either an alpha-meter or a beta-meter.

With the alpha decay, the Iodine releases a helium nucleus, which is an alpha particle. This is very high energy, but travels for a very short distance. There are clinical trials being conducted today where alpha emitters are being used for radioimmunotherapy.

Beta-minus decay emits an electron and an antineutrino. This has very low mass, but has a longer path length than does the alpha particle. Beta-plus decay is what PET scanners use today with the positron emitting radioisotopes. It is very similar to a beta-minus, but the electron with the positive charge annihilates, resulting in the production of a gamma photon.

Gamma photons are also produced with gamma emitters, which are used in nuclear medicine today for cardiac studies and oncology studies.

This report discusses, for the most part, beta decay, because that is the type of treatment that is associated with radioimmunotherapy. In beta decay, a neutron inside the nucleus of an atom breaks down and changes to a proton, emits an electron, and then the atomic number goes up by one and the mass number remains unchanged.

It is understood that beta emission from radioisotopes allows us to kill tumor cells, but that it will also kill normal cells. So as the blood circulates through the bone marrow, there's beta decay from the radioisotope, and there is radiation that is being delivered to the bone marrow cells. In the case of normal bone marrow without lymphoma involvement, there appears to be less radiation to the bone marrow, compared to patients who have significant involvement of lymphoma in the bone marrow.

One of the more important points to understand about radioimmunotherapy is the conjugation, which is the chemical linkage of the radioisotope to the antibody. This linkage is what allows the therapy to be delivered to the tumor cell. If there is a weak linkage, the radioisotope separates from the antibody, resulting in the radioisotope no longer being delivered to the tumor cell, but instead being deposited in an organ or being skewed from the body.

In circumstances where an isotope comes off the antibody, and some of the isotope will come off in any sort of conjugation, the yttrium-90 goes to the bone and I-131 goes to the thyroid and stomach, so they have different routes of excretion following release of the isotope from the antibody. Significant advances in the area of isotope conjugation have been made over the last 20 years in terms of radioimmunotherapy or in terms of targeted therapy. We now have excellent conjugation methods to attach the radioisotope to the antibody.

In the case of Y-90, conjugation is achieved using key molecules which hold the isotope, and which are in turn bound to the antibody.

In the case of I-131 labeling, the I-131 itself is chemically linked to the antibody. There is not a conjugated molecule, but rather a direct linkage -- a chemical bond -- and there are several different methods for accomplishing that. The I-131 conjugation methods, then, generally require some sort of separation of the free isotope from the antibody once the labelling is completed.

If you look at the two radioisotopes that are primarily being used in radioimmunotherapy, you will see that Y-90 does not have a gamma emission, which is good and bad. It cannot be imaged directly, so if the way that this is being used requires an image to be made, you would have to use another isotope. Indium-111, which is very similar to Y-90 and binds similarly with the conjugation, is imagable, and has been used for this purpose. I-131 does have a gamma emission, and can be imaged with a gamma camera. The disadvantage to the gamma emission is that when you begin to look at protection and release of patients from the hospital, the gamma emission requires that patients receiving higher doses of I-131 have to have restrictions on their living patterns or remain in the hospital after treatment. The lack of a gamma emission from Y-90 is helpful in patients in that they can go directly home.

In terms of releasing individuals after we have a pharmaceutical administration of a gamma emitter, there have been new rules that have been written and are in effect. In many places in the United States, an individual can be released once the radiation dose is calculated to be less than 500 mg or 0.5 grams. What this means is that once a patient receives a therapeutic dose of radioisotope, if there is enough gamma emission to give off more than 100 mg, the patient then has to have written instructions given and cannot be released until the point where they are unlikely to give someone else 500 mg. These rules really apply to I-131 labeled antibodies. The yttrium-90 antibody really has very few restrictions due to the fact that there is no gamma emission being given off from the radioisotope.

Another factor to consider in the beta emissions of Y-90 and I-131 is path length. Y-90 has a longer path length, with about 90% of the energy being deposited within 5 mm, compared to about 1 mm with I-131. The longer path length of Y-90 means that larger tumors may receive a higher dose of radiation, but also that adjacent normal cells could receive more radiation from the Y-90, compared to I-131.

Studies of radioimmunotherapy for non-Hodgkin's lymphoma using the yttrium-labeled antibody Zevalin have been conducted. In these studies, patients received rituximab pretreatment with a cold antibody, followed by the indium-labelled Zevalin for imaging. The reason the indium-labelled Zevalin is used is because you cannot image the yttrium. On day seven, then, patients who met the criteria for treatment went ahead and received an additional dose of rituximab pretreatment, followed immediately by the yttrium 90-labelled Zevalin.

In radioimmunotherapy with the I-131-labeled antibody Bexxar, patients are started on potassium iodide to try to reduce the amount of iodine that would be received by the patient's thyroid. Patients then receive unlabeled antibody, followed by a trace-labelled I-131 antibody. The patients then have whole body imaging done on three occasions over the next week. The imaging data is then used to calculate the dose of radiolabeled antibody, which tends to be 65-75 cGy, depending on platelet counts. This treatment dose is preceded again by a dose of the unlabelled antibody. The best way to dose the antibodies is still under investigation. I think the biodistribution of the Y-90 and the I-131 labelled antibodies help dictate which one will need to have the dose calculated based on the excretion date and which one may not.

The I-131 antibodies have significantly more whole-body excretion compared to Y-90. The urinary excretion for Y-90 is about 5-11% over a week, compared to 46-90% at 48 hours for the I-131 antibodies. So there is more of I-131 that is coming off of antibodies, or at least more being secreted from the body, making it more important to do the scans to determine appropriate dosing for patients treated with I-131.

With Y-90, the radioisotope really ends up in either the liver, spleens or a tumor; very little of it comes out of the body. Accordingly, the dosimetry of whole-body clearance does not appear to be required to determine Y-90 radioimmunotherapy dosing.