Daniel J. Macey

Treatment of a patient with B cell lymphoma by I-131 LYM-1 monoclonal antibodies.

A patient with Richters syndrome, a malignant lymphomatous transformation of chronic lymphocytic leukemia, had become moribund with rapidly enlarging masses, granulocytopenia and thrombocytopenia despite the use of conventional chemotherapy and radiotherapy. Greater than ten percent of a test dose of I-131 Lym-1, a murine monoclonal antibody produced against Burkitts African B cell lymphoma, was accumulated by her tumor. The patient was subsequently treated with a series of injections of I-131 Lym-1 with dramatic clinical response, reduction of tumor volume by x-ray computerized tomography and progression of circulating cellular elements toward normality. Her course over the next ten months was not like that to be expected for Richters syndrome, which has an average survival of four months. This mode of treatment appears promising.

Requirements for a treatment planning system for radioimmunotherapy

Cancer-seeking antibodies carrying radionuclides can, in theory, be very powerful agents for the radiotherapy of cancer. However, as with all radiotherapy, the undesired dose to critical normal organs is the limiting factor that determines success or failure. The distribution of radiation dose in cancer and noncancer tissue is highly dependent on choices the therapist can make: choices of the antigens to be targeted, choices of the antibodies or antibody fragments to be used, choices of radionuclides, of amounts, of timing, and other electives. New technologies, especially of monoclonal antibody production, make the options myriad. Optimization of this therapy depends on a foreknowledge of the radiation dose distributions to be expected. The necessary data can be acquired by established tracer techniques, in individual patients, for particular treatment selections. These tracer techniques can now be implemented by advanced equipment for quantitative, tomographic radionuclide imaging and strengthened by dynamic modeling of the physiological parameters which govern radionuclide distribution, and hence radiation dose distribution.

Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy

Myelotoxiclty is the dose-limiting factor in radioimmunotherapy. Traditional methods most commonly used to estimate the radiation adsorbed dose to the bone marrow of patients consider contributions from radionuclide in the blood and/or total body. Targeted therapies, such as radioimmunotherapy, add a third potential source for radiation to the bone marrow because the radiolabeled targeting molecules can accumulate specifically on malignant target cells infiltrating the bone marrow. A non-invasive method for estimating the radiation absorbed dose to the red marrow of patients who have received radiolabeled monoclonal antibodies (MoAb) has been developed and explored. The method depends on determining the cumulated activity in three contributing sources: 1) marrow; 2) blood; and 3) total body. The novel aspect of this method for estimating marrow radiation dose is derivation of the radiation dose for the entire red marrow from radiation dose estimates obtained by detection of cumulated activity in three lumbar vertebrae using a gamma camera. Contributions to the marrow radiation dose from marrow, blood, and total body cumulated activity were determined for patients who received an I-131 labeled MoAb, Lym-1, that reacts with malignant B-lymphocytes of chronic lymphocytic leukemia and nonHodgkins iymphoma. Six patients were selected for illustrative purposes because their vertebrae were readily visualized on lumbar images. The radiation doses to the marrow contributed by nonpene-tratlng emissions in the marrow blood and penetrating emissions in the total body were similar in these patients with a mean of 0.2 and 0.3 rads per administered mCi from the blood and total body, respectively. However, the radiation doses to the marrow from nonpenetrating emissions of I-131 that targeted marrow malignancy varied greatly and ranged from 0.6–2.9 rads per administered mCi in these selected patients. The latter source of marrow radiation dose was often greater than the combined contribution of the blood and total body to marrow radiation dose; this source of marrow radiation dose is ignored by traditional approaches to bone marrow dosimetry and is important to consider for targeted therapies such as radioimmunotherapy. Although it is not appropriate to suggest that the marrow radiation doses estimated using the novel imaging method described are accurate, their use did predict greater hematologic toxicity in the 6 patients and this toxlcity was not anticipated from the marrow radiation doses estimated by using the traditional blood and total body contributions. The exact role of the imaging method remains to be determined and additional validation is required. Although further comparisons with data for hematologic toxicities and results from bone marrow biopsies are required, the method has the potential for providing the therapist with a predictor of greater likelihood of myelotoxicity. Imaging studies with the intended therapeutic agent can be obtained for an individual patient so that predictions can be made before the implementation of therapy.

Quantitative imaging of mouse L-6 monoclonal antibody in breast cancer patients to develop a therapeutic strategy

L-6, a mouse IgG2a anti-adenocarcinoma monoclonal antibody (MoAb) with favorable immunopathology and mouse biokinetics, was evaluated for cancer radioimmunotherapy by pharmacokinetic studies in 10 patients with breast cancer. The effect of escalating the preinfused protein dose was studied in two patients at each level, using 50, 100, 150, 200 and 400 mg of unlabeled L-6 prior to a 10 mCi imaging dose of 131I L-6. Quantitative imaging, and blood and urine clearances were obtained. After the 50 mg preinfusion, rapid blood clearance and lung extraction of the radiopharmaceutical occurred immediately post injection. Greater preload amounts of L-6 were associated with an increase in the intercept of the slow phase of the blood clearance from 17 to 22% injected dose (ID) with 50 mg to 70 to 80% ID with 400 mg (P less than 0.01). Lung uptake of the radiopharmaceutical immediately post injection decreased from 15 to 19% ID (50 mg) to 6 to 8% ID (400 mg). Tumors were visualized only after larger L-6 preloads, but in these patients small chest tumors contained 0.6-1.2% ID (0.1% ID/g maximum). This study suggests that L-6 reactive sites that are readily available in the lung can be saturated, so that a subsequent dose of I-131 L-6 is delivered to the tumor. This approach provides a new strategy for developing an effective method for radioimmunotherapy using a MoAb that has some cross-reactivity. Quantitative imaging contributed to detection of the cross-reactivity and the strategy for overcoming it.

Quantitative SPECT of uptake of monoclonal antibodies

Absolute quantitation of the distribution of radiolabeled antibodies is important to the efficient conduct of research with these agents and their ultimate use for imaging and treatment, but is formidable because of the unrestricted nature of their distribution within the patient. Planar imaging methods have been developed and provide an adequate approximation of the distribution of radionuclide for many purposes, particularly when there is considerable specificity of targeting. This is not currently the case for antibodies and is unlikely in the future. Single photon emission computed tomography (SPECT) provides potential for greater accuracy because it reduces problems caused by superimposition of tissues and non-target contributions to target counts. SPECT measurement of radionuclide content requires: (1) accurate determination of camera sensitivity; (2) accurate determination of the number of counts in a defined region of interest; (3) correction for attenuation; (4) correction for scatter and septal penetration; (5) accurate measurement of the administered dose; (6) adequate statistics; and (7) accurate definition of tissue mass or volume. The major impediment to each of these requirements is scatter of many types. The magnitude of this problem can be diminished by improvements in tomographic camera design, computer algorithms, and methodological approaches.

Comparison of Biodistribution, Dosimetry, and Outcome from Clinical Trials of Radionuclide-CC49 Antibody Therapy

CC49 is a second-generation murine antibody with anti-TAG-72 (tumor-associated antigen) reactivity. For cancer therapy, it has the advantage of being expressed on adenocarcinomas but not on most normal tissues. CC49 has been utilized in phase I and II clinical trials at multiple institutions. Therapeutic applications to date have included (131)I-, (90)Y-, and (177)Lu-CC49, with tracer amounts of (111)In-CC49 as a dosimetry surrogate for (90)Y-CC49 therapy. Dosimetry methods and details of their description vary between studies. Biodistribution to normal organs and the effective plasma T(1/2) for various radionuclides were relatively consistent among patients with different diseases and treatment at several institutions. As expected with marrow suppression being the dose-limiting toxicity, higher doses of (177)Lu-CC49 were tolerated via intraperitoneal than IV administration. The biologic response modifier interferon enhanced TAG-72 expression and resulted in a trend of increased uptake of (131)I-CC49 by tumors. Tumor dose estimates were more variable than that of normal organs. Standardization and improved dosimetry may be helpful for comparison among patients in various studies and for establishing dose/toxicity relationships that are useful for predicting safe levels of radioimmunoconjugates.

The Design of a Radiolabeled Monoclonal Antibody for Radioimmunodiagnosis and Radioimmunotherapy

Monoclonal antibodies have become recognized as promising carrier molecules for the development of target specific radiopharmaceuticals. Since the hybridoma technology can be used to discriminate small epitopes on products of either normal or abnormal cells and to produce antibodies which react uniquely with those epitopes, a new generation of biologic targets are being sought on hormones, hormone precursors, myosin, fibrin, blood cells, infectious agents, tumor cells, tumor associated antigen products and so forth. Although critical for ultimate imaging and therapeutic success, epitope recognition and appropriate target selection is only the first step toward immunologically derived radiopharmaceuticals.

A Modified Post Processing Correction Matrix For SPECT

A post reconstruction method of attenuation compensation for Single Photon Emission Computed Tomography (SPECT) has been investigated that offers a new approach to the problem of quantitation. A modified correction matrix is generated for attenuation compensation in which the Linear Attenuation Coefficient (LAC) for each pixel is assigned a value depending on the radial distance of the pixel from the true section boundary. Attenuation compensation of transverse section images of small and large volume sources of Tc-99m in phantoms using this modified matrix indicated that a known quantity of radionuclide could be determined to better than 10%. The scatter fraction was estimated as the difference in the corrected section images using a multiplicative matrix generated with a constant LAC for each pixel and the modified matrix proposed in this report.