Low-dose, fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody.

PURPOSE: This trial was conducted to assess the toxicity and efficacy of 131I-Lym-1 in patients with either malignant B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) using low-dose, fractionated radioimmunotherapy (RIT). MATERIALS AND METHODS: Thirty adult patients who had advanced B-cell malignancies (25 NHL and 5 CLL) had progressed despite standard therapy; 12 patients entered the trial with Karnofsky performance status (KPS) of equal to or greater than 60. Patients were treated with a series of intravenous doses of 131I-Lym-1 with a goal of reaching a cumulative dose in each patient of at least 300 mCi. All patients were Lym-1 reactive. Clinical responses and immediate toxicity were evaluable in all 30 patients and delayed toxicity in 26. RESULTS: Toxicity to Lym-1 antibody occurred with 28% of the 176 doses and was transient. Human antimouse antibodies (HAMA) were generated in 30% after a mean of 4 doses, but interrupted therapy in only 10% of the patients. Thrombocytopenia was dose-limiting; there were no deaths due to toxicity. Tumor regression occurred in 25 (83%) of the patients and was great enough, and durable enough, in 17 (57%) to qualify them as responders; 13 NHL patients and 4 CLL patients. Advanced disease often interrupted therapy prematurely. However, 18 patients received at least 180 mCi of 131I-Lym-1; 17 (94%) of these responded to the therapy. CONCLUSION: Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.

Radioimmunotherapy for advanced breast cancer using I-131-ChL6 antibody.

BACKGROUND: The biologically active, antiadenocarcinoma monoclonal antibody chimeric L6 (ChL6) was labeled with 131I and administered in cycles to patients with metastatic breast cancer who had failed standard therapy. The therapeutic potential, tumor targeting and maximum tolerated dose of 131I-ChL6 were studied. METHODS: Ten patients with L6 reactive breast cancer received an imaging dose of 131I-ChL6 followed 24 hours later by a therapy dose of 131I-ChL6 (20-70 mCi/m2). Patients received up to 4 monthly cycles unless they had significant myelosuppression, progression of disease, or a high human anti-mouse antibody titer. In vivo activation of effector cell function, complement levels and cytokine release were studied. RESULTS: All 10 patients had detectable cancer on the imaging study. In 7 patients with superficial cancer, the radiation dose was 120 to 3700 cGy/cycle; 5-30 times higher than the whole body dose. Therapy resulted in minimal acute or subacute toxicity. Dose limiting toxicities were neutropenia and thrombocytopenia. Six of 10 patients had clinically measurable tumor responses; 5 had responses that lasted more than one month (1.5-5 months). The MTD for 131I-ChL6, given in at least two monthly doses, was 60 mCi/m2. CONCLUSION: Objective clinical responses were seen in five of 10 patients treated with 131I-ChL6. The tumor response in heavily pretreated, advanced breast cancer may be related to the combined effects of targeted radiation and the biological activity of L6/ChL6.

Radioimmunotherapy for breast cancer using escalating fractionated doses of 131I-labeled chimeric L6 antibody with peripheral blood progenitor cell transfusions.

Radioimmunotherapy (RAIT) using a humanized murine monoclonal antibody, chimeric L6 (ChL6), has produced objective tumor reduction in 50% of chemotherapy-refractory patients with metastatic breast cancer in our prior studies. Because myelosuppression limited dose escalation, we evaluated the ability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cell (PBPC) transfusions to ameliorate this problem. 131I-labeled ChL6 was given at a starting dose of 150 mCi/m2 (2,5 times the maximum tolerated dose without PBPCs) for a planned three treatments. When blood radioactivity declined to less than 1 microCi/ml after treatment, PBPCs were transfused, and G-CSF was administered. Patient 1 had minimal myelosuppression, received two cycles of therapy, and then developed human antimonoclonal antibody (HAMA). Patient 2 had prolonged thrombocytopenia that resolved after additional PBPC transfusion. Progressive disease as well as HAMA prevented further treatment. Patient 3 received all three cycles of 150 mCi/m2 at 8-week intervals. Thrombocytopenia (< 25,000/microliter) occurred but was transient (0-7 days). Because HAMA developed in all prior patients who received G-CSF with ChL6 RAIT, including patients 1 and 2, who received PBPC, patient 3 was given cyclosporin for 14 days. She did not develop HAMA or significant toxicity following 3 cycles of RAIT. Cumulative radiation doses to her lungs and tumor were estimated at 3,100 and 11,200 cGy, respectively. For 9 months, she had a reduction in bone pain, a decline in serum tumor markers, and decreased tumor uptake of F-18-deoxyglucose on a positron emission scan. Her performance status improved, and she had no pulmonary toxicity. We conclude that: (a) PBPC transfusion can modify the myelotoxicity of RAIT and can permit repetitive dosing; (b) cyclosporin is a promising means to abrogate HAMA; and (c) fractionation of intensive-dose RAIT may increase the antitumor effect and reduce normal organ toxicity.

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. METHODS: Five patients with refractory chronic lymphocytic leukemia were treated with a novel radioimmunoconjugate, 131I-Lym-1, reactive with antigenic sites on malignant B lymphocytes. 131I-Lym-1 was given to the patients in doses of 20-65 mCi at 2-6-week intervals. RESULTS: Radioimmunoconjugate treatment using 131I-Lym-1 induced objective responses with dramatic reduction in lymphadenopathy and, in two patients, normalization of leukocyte counts. However, lymphocytes continued to be the dominate cells in the peripheral blood and bone marrow. Because these patients had advanced disease associated with preexisting peripheral cytopenias, requiring repeated transfusions, and recurrent infections, hematopoietic toxicity from 131I-Lym-1 was difficult to evaluate. The patients seemed to tolerate at least 200 mCi of 131I given at these dose levels, and intervals before toxicity added to their existing peripheral cytopenias. Radionuclide doses in excess of 300 mCi aggravated preexisting thrombocytopenia. CONCLUSION: Although the data raise the possibility of a role for 131I-Lym-1 monoclonal antibody in the treatment of chronic lymphocytic leukemia, strategies to address the radionuclide-induced thrombocytopenia are essential before this intervention can become a clinically useful therapeutic modality for chronic lymphocytic leukemia.

The biologic window for chimeric L6 radioimmunotherapy.

BACKGROUND: There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received 131I chimeric-L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement-dependent tumor cytolysis with human serum, and antibody-dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a "therapeutic window" of increased vascular permeability, allowing more 131I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6. METHODS: Nine patients with metastatic breast cancer were treated on a therapy protocol and received imaging and therapy doses of 131I ChL6 on two sequential days at 4 week intervals. During each treatment cycle, serum cytokines, complement, albumin, and 131I ChL6 blood clearance were monitored, peripheral blood mononuclear cell activation was assessed, and tumor uptake and response were documented. RESULTS: After L6 or ChL6 was infused, patients demonstrated immediate serum-complement activation, manifested by rapidly decreasing levels of serum complements 3 and 4. Tumor uptake of the second 131I MoAb (therapeutic) injection, given after the second daily injections of 200 mg MoAb, was usually higher than the tumor uptake of the first 131I MoAb (imaging) dose given after a single 200 mg infusion of MoAb. Although serum complement frequently decreased after the first 50-100 mg dose of L6 or ChL6, elevation of soluble interleukin-2 receptor (IL-2R) in serum was seen only in patients who received 150 mg or more of L6 or ChL6. In the nine treated patients, with only one exception, the higher grade of therapeutic tumor response was seen in patients with a greater increase in IL-2R levels. CONCLUSIONS: The clinical importance of understanding these mechanisms is emphasized by the occurrence of measurable tumor regressions in five of the first nine advanced metastatic breast cancer patients treated in this manner. Absence of pulmonary edema and delayed release of dose-dependent IL-2R suggest that targeting of the pulmonary endothelium by L6 or ChL6 is not the major cause of the observed biologic effects. This unique response of a solid tumor to radioimmunoconjugate therapy may be secondary to both the increased delivery of the radioimmunoconjugate to tumor cells caused by enhanced vascular permeability, and to synergistic effects of radiation and activated effector cell mechanisms.

Overview of radioimmunotherapy in advanced breast cancer using I-131 chimeric L6.

131I chimeric L6 (ChL6) monoclonal antibody (MoAb) therapy has been performed in 12 patients with advanced, metastatic breast cancer. The protocol was designed to determine the maximum tolerated dose (MTD) of radioimmunotherapy that could be administered at 4 intervals. Ten patients received 20-70 mCi/m2 of 131I ChL6. Two of the patients received granulocyte colony stimulating factor (GCSF) on days 10-20 post therapy. The MTD for two doses was 60 mCi/m2 and thrombocytopenia was the dose limiting toxicity in the absence of marrow reconstitution with stem cells. Two patients received 150 mCi/m2 with autologous peripheral blood stem cell support 7 and 9 days post treatment. The MTD has not been reached for 131I-ChL6 with autologous stem cell support. In the 12 patients treated with 131I ChL6, six patients (50%) had measurable tumor regressions greater than 30% of the sum of the largest two dimensional products for measurable tumors. Four of these 6 patients had a partial response (PR), i.e., > or = 50% reduction in tumor size. These therapeutic responses associated with modest clinical toxicity in heavily pretreated patients suggest that clinically relevant radioimmunotherapeutic approaches can be devised for metastatic breast cancer.

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 lgG1 monoclonal antibody to adenocarcinoma. Initially, an imaging 10 mCi dose of I-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 patient's 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.

Fractionated radioimmunotherapy of B-cell malignancies with 131I-Lym-1.

Eighteen patients with Stage 4 B-cell malignancies, which were primarily of intermediate or high grade and progressive despite multiple drug chemotherapy and external irradiation, were treated with fractionated doses of 131I-labeled Lym-1. Lym-1 is an IgG2a monoclonal antibody that was produced by immunizing mice with Raji cell nuclei that originated from a patient with African Burkitt's lymphoma. Despite advanced disease, 10 of the patients had objective evidence for a complete or partial remission. Toxicity was very modest except in one patient who developed hypotension. Dose-dependent hepatic uptake of Lym-1 was observed in the patients and in BALB/c mice suggesting receptor-mediated recognition of this murine antibody.

Treatment of B cell malignancies with 131I Lym-1 monoclonal antibodies.

Lym-I is a murine IgG2a monoclonal antibody (MAb) that is B-cell specific but has greater avidity for malignant B cells when compared with normal B lymphocytes. It was originally produced by immunizing mice with nuclei of cultured cells from a patient with Burkitt's lymphoma. Ten patients with progressive refractory B-cell malignancies were treated with 131I-labelled Lym-I. Treatment with 131I Lym-I produced complete or partial remissions in 4 patients. Toxicity did not occur or was mild in most patients. The only significant complications included two instances of fistula secondary to necrotic lymphoma and one instance of hypotension. Human antimouse antibodies occurred in only 2 patients after multiple injections of Lym-I antibody. This experience was in contrast to treatment of B-cell malignancies with unconjugated Lym-I alone. Unconjugated Lym-I also caused no significant toxicity but was less effective than 131I Lym-I.

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.

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

A patient with Richter's 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 Burkitt's 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 Richter's syndrome, which has an average survival of four months. This mode of treatment appears promising.

Radiolabelled monoclonal antibodies for the detection of cancer.

Methods currently available to the clinician for the detection and localization of cancer are not specific and may have reached their technical limits. Deficiencies of these methods are detailed, and an ideal system for cancer detection is presented. Monoclonal antibodies directed against tumor antigens and labelled with radionuclides approach the ideal as a method for cancer screening, detection, localization, monitoring, and, perhaps, therapy. The production and radiolabelling of monoclonal antibodies are reviewed, and recent technical developments for imaging are explained. Methods to manipulate the system to achieve specific goals are outlined, and examples are shown. Metastases of certain tumors are demonstrated. The method holds great potential for diagnosis, monitoring, and even for radiotherapy of target tumors. Clinical trials are now in progress.

Technetium-99m NGA functional hepatic imaging: preliminary clinical experience.

Technetium-99m galactosyl-neoglycoalbumin ( [Tc]NGA) is a radiolabeled ligand to hepatic binding protein, a receptor which resides at the plasma membrane of hepatocytes. This receptor-binding radiopharmaceutical and its kinetic model provide a noninvasive method for the assessment of liver function. Eighteen patients were studied: seven with hepatoma, eight with liver metastases, four with cirrhosis (two had concurrent hepatoma and one chronic active hepatitis), and one patient with acute fulminant non-A, non-B hepatitis. Technetium-99m NGA liver imaging provided anatomic information of diagnostic quality comparable to that obtained with other routine imaging modalities, including computed tomography, angiography, ultrasound, and [Tc]sulfur colloid scintigraphy. Kinetic modeling of dynamic [Tc]NGA data produced estimates of standardized hepatic blood flow, Q (hepatic blood flow divided by total blood volume), and hepatic binding protein concentration, [HBP]. Clinical correlation was by classical Child-Turcotte criteria (CTC). Significant rank correlation was obtained between [HBP] estimates and CTC scores (rs = -0.72, p = 0.001). This correlation supports the hypothesis that [HBP] is a measure of functional hepatocyte mass. The combination of decreased Q and markedly reduced [HBP] may have prognostic significance; all three patients with this combination died of hepatic failure within 6 wk of imaging.

Use of immunologic markers in obscure hematologic disease.

Tumor cells from two patients with very different clinical diseases were evaluated using immunologic techniques. The first patient had a persistent T-cell lymphocytosis and other symptoms suggestive of T-cell malignancy. She also had an adnexal mass. Following surgical excision, the mass was identified as a benign teratoma that contained thymic tissue. The T-cell lymphocytosis subsided following removal of the mass. The second patient had leukemia, the cells of which were morphologically identified as myelomonocytic. Surface marker studies, however, showed the presence of monoclonal surface immunoglobulins. Enzymatic digestion of the cells showed that the antibodies were cytophilic and not produced by the tumor population. These studies emphasize the value of immunologic techniques in characterizing tumor cells.

A breast self-examination program for high school students.

Breast self-examination (BSE) is an important adjunct to the detection of breast cancer at an early stage. High school students were instructed in the importance and methods of BSE. By use of questionnaires, the program was evaluated for interest, acceptability, and compliance. It was found that high school students were not adverse to learning about BSE, found the program acceptable, and maintained some compliance at one year.

Patterns of exogenous and endogenous hematopoietic repopulation following radiation injury.

Patterns of hematopoietic recovery in mice given an LD50/30 radiation exposure were different from those in animals given an LD100/30 exposure and a marrow transplant sufficient to effect 50 per cent 30-day survival. Death occurred later, and recovery of some peripheral blood elements was delayed in the LD50/30 mice. Over the period of study, splenic hematopoiesis and stem cell renewal were insignificant in the LD50/30 mice yet were active in the marrow-transplanted animals. The slow recovery of erythropoiesis in the LD30/30 mice is explained in part by the lack of early splenic hematopoiesis. This effect appeared to be attributable to the splenic microenvironment which, although being suitable for growth of unirradiated hematopoietic cells, was not conducive to repair of radiated splenic hematopoietic cells.