Radiation therapy has seen a steady increase in the precision of delivery to the cancer and the exclusion of normal tissues from the field. Computers now design portals for external beam radiation, and intensity-modulated radiation and interstitial brachytherapy are growing in popularity. The newest method links the radiation source to a "cancer-seeking" antibody, thereby combining the antitumor benefits of irradiation with the immune-mediated cytotoxic effects of antibodies. Several options for such radioimmunotherapy are possible, and one agent has been approved for marketing.

DESIGNING RADIOIMMUNOTHERAPY

For radioimmunotherapy to be successful, a cancer must bear an accessible antigen that, ideally, is present only on that cancer. Because such antigens are rare, product developers have targeted proteins expressed to a greater extent on cancers than on normal tissues. Some examples are the MUC-1 glycoprotein, detectable in more than 90% of breast cancers; carcinoembryonic antigen (CEA), which is overexpressed on many tumors; and the CD20 and CD22 antigens of mature B lymphocytes, which characterize many lymphomas.

Even if perfect specificity were achievable, targeting would not be perfect. Antibodies are proteins that are extracted from the blood by the kidneys and the liver. Therefore, an early test of antibody localization and definition of the renal and hepatic radiation doses are important.

Once a target is identified, a monoclonal antibody must be created that is highly specific and of high affinity and avidity. These antibodies come from mouse hybridoma cell lines and so will induce antibodies in patients (human anti-mouse antibodies; HAMA). If only a single dose of an antibody will be given, HAMA will be of no consequence, but repeated doses carry a risk of adverse immunologic effects and reduced efficacy caused by binding to HAMA. Therefore, the antibody may be modified to consist entirely or partially of human proteins. In the former case, it is said to be humanized; in the latter, it is called chimeric.

The next question is what radioisotope to use. Iodine 131 is familiar but is not easy to handle. Yttrium 90, a high-energy beta emitter, delivers higher doses of radiation, but it is not suitable for imaging, so a preliminary scan with another radionuclide, indium 111, is used to determine the dose (see box, page 24). Rhenium 186 has been used against head and neck cancer (see below). Again, the isotope is not useful for imaging, necessitating a preliminary scan with 99mTc. Radiometals such as copper 67 may be more effective than either iodine or yttrium.¹ Some work also has been done with two lanthanide elements, holmium 166 and lutetium 177 (a member of the yttrium family). The ideal isotope for a particular situation depends on the antibody and on the size and accessibility of the tumor burden.^2,3

With suitable targets and antibodies, excellent localization and high radiation doses can be achieved. For example, in patients with advanced non-Hodgkin's lymphoma who were given a ⁹⁰Y-labeled antilymphoma antibody, the tumor-to-marrow ratio was 66:1 and the tumor-to-liver ratio was 1:1.⁴ The dose delivered to the tumors averaged 6.57 Gy.⁴ In patients with metastatic prostate cancer, the mean radiation dose to the lesions from a ⁹⁰Y-anti-adenocarcinoma antibody was 10.5 Gy.⁵

NON-HODGKIN'S LYMPHOMA

The first radioimmunotherapeutic approved by the US Food and Drug Administration is ⁹⁰Y-ibritumomab-tiuxetan, which targets the CD20 antigen. The product is indicated for the treatment of certain relapsed or refractory B-cell non-Hodgkin's lymphomas in patients who have no more than 25% of their marrow involved with disease. Patients undergo a preliminary study with ¹¹¹In-ibritumomab followed by gamma camera studies to confirm that the monoclonal antibody will be distributed appropriately in the body. The entire treatment protocol takes 7 to 9 days, but it can be delivered on an outpatient basis with minimal risk to close contacts.⁶ In registration trials, overall response rates as high as 80% with complete response rates of 15% to 30% were found.⁷ Rituximab, which has the same target but does not deliver radiation, produced a response rate of 56% with a complete response rate of 16%. The effect of ⁹⁰Y-ibritumomab-tiuxetan on long-term survival is not yet known.

Another product for non-Hodgkin's lymphoma, ¹³¹I-tositumomab, has run into difficulties at the FDA. This antibody also targets CD20. In a pivotal clinical trial in 60 patients, the agent produced a response rate of 65% with a complete response rate of 20%.⁸ The median duration of the response was 6.5 months; in the patients obtaining a complete response, the median duration had not been reached at 47 months. In contrast, the last chemotherapy (the patients had received a median of four previous regimens) had produced a response rate of 28% with the median duration being 3.4 months. Despite the complexities of dosing with this product (see box, page 24), it can be administered on an outpatient basis without violating the Nuclear Regulatory Commission guidelines on radiation exposure of contacts.⁹

Because these antibodies target antigens expressed on blood cells and some precursors, the most common adverse effect is cytopenia that can lead to bleeding and infection. The effect lasts about 2 months. A few patients have gone on to have myelodysplastic syndrome.

OTHER CANCERS

Several other cancers are candidates for radioimmunotherapy. Antibodies and peptides that have already been approved for imaging or are in late-stage clinical trials for that purpose are being redesigned for therapeutic use. Some of the cancers being targeted are colorectal, head and neck, thyroid, breast, ovary, and lung.

In a study at Georg August University in Gottingen, Germany, patients with metastatic colorectal cancer received the maximum tolerated dose of a ¹³¹I-tagged anti-CEA antibody.¹⁰ Of the 19 assessable patients with measurable refractory lesions, three had partial remissions and eight had minor responses that lasted as long as 15 months. Among nine patients who received the antibody as an adjuvant after resection of all known liver metastases, seven had been free of disease for as long as 36 months at the time of the report. Historically, recurrences would have been expected in six patients. Two of the four evaluable patients who received a second dose of the antibody had partial remissions without unusual toxicity. These investigators stressed the importance of restricting radioimmunotherapy to patients with small volumes of disease.

A team at the University Hospital Vrije Universiteit in Amsterdam used a ¹⁸⁶Re-tagged chimeric antibody in a dose-escalation Phase I study in 13 patients with recurrent or metastatic squamous-cell carcinoma of the head and neck, finding disease stabilization for 6 months in a patient who received the maximum tolerated dose.¹¹ O'Donnell and coworkers applied radioimmunotherapy for palliation of pain associated with metastases from prostate cancer.⁵ Seven of the 13 patients reported partial or complete relief for an average of 4 weeks after a single dose of a ⁹⁰Y-tagged antibody. Investigators at the Garden State Cancer Center in Belleville, NJ, and St Joseph's Hospital and Medical Center in Paterson tested ¹³¹I-anti-CEA and autologous hematopoietic stem cell rescue in 12 patients with rapidly growing metastatic medullary thyroid cancer.¹² Because the thyroid gland normally concentrates iodine, one would expect this technique to deliver a particularly high dose of radiation, as both the radioisotope and the monoclonal antibody would be attracted to the tissue. Indeed, all of the patients demonstrated some response: a partial remission for 1 year in one, a minor response for 3 months in another, and disease stabilization for as long as 16 months in 10 patients.

POSSIBLE REFINEMENTS

Uptake of antibody might be enhanced by increasing the permeability of the blood vessels within the tumor. In mice with human breast cancer xenografts, administration of a peptide that targets the alpha v beta 3 integrin receptor, a protein strongly expressed in tumor neovessels, caused a 40% to 50% increase in the uptake of a monoclonal antibody.¹³ When the antibody was tagged with ⁹⁰Y, a 57% cure rate was obtained, whereas no cures were seen with antibody without the permeability-increasing peptide.¹⁴

Taxanes increase cellular sensitivity to radiation, making them a logical adjuvant to radioimmunotherapy. A ⁹⁰Y-tagged monoclonal antibody plus paclitaxel cured 88% of mice with human breast cancer xenografts, whereas the cure rate with the radioantibody alone was 25%.¹⁴ In mice with prostate cancer xenografts, the cure rate was 67% in animals given docetaxel before administration of a ⁹⁰Y-tagged antibody, whereas there were no cures with the radioantibody alone.¹⁵

In one of the few clinical trials of combination therapy, investigators at the University of Alabama and the Wallace Tumor Institute in Birmingham gave interferon-alpha to women with recurrent or persistent ovarian cancer to induce greater expression of a tumor-associated antigen.¹⁶ The patients then received intraperitoneal paclitaxel before radioimmunotherapy with a ¹⁷⁷Lu-tagged antibody. Four of the 17 patients with measurable disease had partial responses, and four of the 27 patients with confirmed but not measurable disease had progression-free intervals ranging from 18+ to 37+ months.

Fractionated treatment would permit better tailoring of the dose to the individual patient, raise the maximum tolerated dose by reducing toxicity, and improve the uniformity of tumor exposure to radiation.¹⁷ However, the logistical and economic implications of fractionated radioimmunotherapy are significant, and considerable research remains to be done on the number and size of the doses and the dosing interval before such an approach can be recommended.

Clinical trials are in progress of another method of increasing the radiation dose. Here, a ¹³¹I-labeled monoclonal antibody against tenascin-C (an extracellular matrix protein expressed in gliomas, particularly those of higher grade) is instilled into the cavity in the brain left by resection. Patients then receive external beam radiotherapy and 1 year of chemotherapy. In a Phase II trial, the median survival was 87 weeks for the whole series and 79 weeks for patients with glioblastoma multiforme, far longer than that of historical controls.¹⁸ Moreover, the technique compared favorably with interstitial brachytherapy and stereotactic radiosurgery and was less likely to cause serious radionecrosis.

CONCLUSION

Although cancer is the focus of radioimmunotherapy research at present, the technique may also be applicable to benign conditions such as certain autoimmune disorders (eg, rheumatoid arthritis) or Graves' disease. The recent approval of ⁹⁰Y-ibritumomab-tiuxetan probably is only the beginning.

Judith Gunn Bronson, MS, is a contributing writer for Decisions in Imaging Economics.

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