Lois F. O'Grady

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.

Effect of lym‐1 radioimmunoconjugate on refractory chronic lymphocytic leukemia

Background. Although chronic lymphocytic leukemia is usually indolent and responsive to treatment early in its course, later stages are characterized by inexorable progression despite standard treatment so that new therapies are needed. Because malignant lymphocytes have characteristic surface antigens, the role of monoclonal antibodies is worthy of intensive investigation.

Radioimmunotherapy for breast cancer: treatment of a patient with I-131 L6 chimeric monoclonal antibody.

We report the first treatment of metastatic breast cancer by systemic radioimmunotherapy. The serial therapy doses were chosen based on quantitative imaging data in a treatment planning approach. A terminally ill patient with aggressive, locally advanced breast cancer who had failed radiation treatment and chemotherapy was injected intravenously with radiolabeled I-131 chimeric L6, a human-mouse chimeric IgG1 monoclonal antibody to adenocarcinoma. Initially, an imaging 10 mCi dose of 1-131 chimeric L6 (dose 1) deposited 8.8% of the injected dose in her chest wall tumor at 48 hours. Ten days later the patient was given a 150 mCi I-131 chimeric L6 dose (dose 2) followed three weeks later by a 100 mCi dose (dose 3). Tumor uptake and retention were comparable for doses 1 and 2, and decreased for dose 3. Following dose 3 the patient developed a manageable thrombocytopenia and transient Grade IV granulocytopenia. The tumor was observed to decrease in size with peak tumor regression occurring two weeks after dose 3. This partial response (PR) was achieved by radioimmunotherapy at a time when conventional therapy had been unable to impact the growth of the patients massive and aggressive tumor.

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.

Non-dehalogenation mechanisms for excretion of radioiodine after administration of labeled antibodies.

In patients or mice with cancer the pharmacokinetic behavior of radioiodinated and radiometal chelated antibodies has been observed to be different. Rapid clearance from the tissues and excretion into the urine can occur after injection of radioiodinated antibodies. These observations have been interpreted to reflect in vivo dehalogenation of the antibody. This publication describes a variety of other mechanisms that can underlie these phenomena. These mechanisms include receptor uptake and catabolism of antibody and instability of the labeled antibody due to the labeling conditions. Specifically, the relative masses of chloramine-T and antibody in the iodination reaction mixture, the level of iodination of the antibody, and the amount of antibody administered to the recipient are all factors which can influence the clearance of radioiodinated antibody from the recipient. The final determinant for the different behavior of radioiodinated and In-111 metal chelated antibody relate to the different biologic pathways of indium when compared to iodine

Stem cell renewal in frozen marrow

Summary Bone marrow can be stored at low temperatures with minimal loss of stem cells and no detectable alteration of differentiation capacity or rate of growth of differentiated elements. The present studies demonstrate that hematopoietic stem cells, preserved in either glycerol or dimethyl sulfoxide and cooled to −100°C, replenish their own population at the same time and at the same rate as stem cells from fresh marrow. Murine bone marrow was suspended in Hanks solution containing 4% calf serum and 12% glycerol or dimethyl sulfoxide. The suspensions were cooled at 2°C per min to −100°C, rapidly thawed, and diluted with 35% glucose and 6% dextran. Lethally irradiated mice were injected with comparable numbers of syngeneic cells, either fresh or frozen and thawed. Stem cells, undergoing self-renewal in these mice, were detected by retransplant into other irradiated mice in which they produce grossly visible colonies of hematopoietic tissue. The results indicate that the functional characteristics of transplanted hematopoietic stem cells are unimpaired by this regimen of marrow preservation.