3F8 monoclonal antibody treatment of patients with stage IV neuroblastoma: a phase II study.
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Antibodies, Monoclonal↗
Biomedical subjects
S M Larson
Publications and source records attributed to S M Larson.
In vivo uptake of carbon-14-colchicine for identification of tumor multidrug resistance.
UNLABELLED: A major limitation in the treatment of cancer with natural product chemotherapeutic agents is the development of multidrug resistance (MDR). Multidrug resistance is attributed to enhanced expression of the multidrug resistance gene MDR1. Colchicine (CHC) is known to be one of the MDR drugs. We have previously demonstrated that it is possible to distinguish multidrug-resistant tumors from multidrug-sensitive tumors in vivo on the basis of tritium (3H) uptake following injection of 3H-CHC. METHODS: The present studies were carried out in xenografted animals using 14C-CHC which may be more indicative of 11C-labeled CHC distribution with regard to circulating metabolites, since metabolic processes following injection of (ring C, methoxy-11C)-CHC may produce significant amounts of circulating 1-carbon fragments (i.e., methanol and/or formaldehyde). Experiments were carried out at a dose of 2 mg/kg. RESULTS: Activity concentration per injected dose was approximately twice as great in sensitive as in resistant tumors (p < 0.05) at 60 min following intravenous injection of 14C-CHS. About 75% of total activity was CHC in the sensitive tumors. The findings are further confirmed by the quantitative autoradiographic evaluation of resistant and sensitive tumors. CONCLUSIONS: These studies confirm our previous observations that it is possible to noninvasively distinguish multidrug-resistant tumors from sensitive tumors in vivo based on uptake of an injected MDR drug using a 14C-labeled CHC at the same position and of comparable specific activity to a 11C-CHC tracer used for PET imaging.
Animals↗
Biodistribution and intraoperative evaluation of radiolabeled monoclonal antibody MX35 in patients with epithelial ovarian cancer.
Murine monoclonal antibody (MAb) MX 35 shows strong homogeneous reactivity with more than 90% of epithelial ovarian cancers. Twenty-five patients with advanced ovarian cancer were entered into a clinical trial using 125I- or 131I-labeled MX 35 in doses of 2, 10, or 20 mg administered by intravenous (i.v.) or intraperitoneal injection. All patients underwent laparotomy at 7 to 20 days following MAb injection to assess tumor distribution, obtain biopsies of tumor and normal tissue, and evaluate the use of an intraoperative hand-held gamma-detecting device. Following i.v. injection, serum Mab half-life was 36 hr. Tumor biopsies obtained at surgery showed MAb accumulation of from 6.7 x 10(-3) to 4.0 x 10(-5)% injected dose/g of tissue. There was no correlation between absolute MAb accumulation in tumor and MAb dose administered. Regression analysis showed a correlation between MAb accumulation and the interval between MAb injection and surgery (P = 0.008). Specific localization of MAb in tumor was demonstrated by tumor:normal tissue ratios ranging from 2.3:1 to 34:1 (mean, 10.18:1). The tumor:normal tissue ratios were not significantly related to MAb dose, the level of immunohistochemical antigen expression, or the interval between MAb injection and surgery. Due to the relatively long serum half-life, mean tumor:serum ratios were only 1.53 following IV injection. This ratio did not correlate with MAb dose, days from injection, or antigen expression. There was an excellent correlation (P = 0.001) between MAb uptake, as measured by the intraoperative hand-held gamma counter, and direct gamma counting of excised tissues. MAb MX 35 localizes well to tumor in selected patients with ovarian cancer, and MAb uptake can be reliably quantitated in vivo with the hand-held intraoperative gamma counter.
Antibodies, Monoclonal↗
Characterization of neuroblastoma xenograft in rat flank. I. Growth, interstitial fluid pressure, and interstitial fluid velocity distribution profiles.
The growth, interstitial fluid pressure (IFP) and interstitial fluid velocity (IFV) profiles of a human neuroblastoma propagated in the flank of an immune suppressed rat were characterized. IFP was measured in the tumor center as a function of size, while radial distributions of IFP and IFV were measured in 2-cm tumors. IFP and IFV were measured using the wick-in-needle and clearance of locally generated hydrogen techniques, respectively. These techniques have a high spatial resolution, permit repetitive measurements, and are minimally invasive. We observed that IFP in the neuroblastoma increased as the tumor grew. Furthermore, IFP increased and its IFV decreased from the periphery toward the center of the tumor. Measured IFP and IFV values were compared to theoretical expectations calculated from the Baxter and Jain mathematical model. The predictions were highly correlated to the measured IFP and IFV profiles with the transport impedence parameter alpha 2 = 24.4. From our measurement data and the Baxter-Jain equations, we computed the interstitium hydraulic conductivity for neuroblastoma to be 7.11 x 10(-6) cm2/mm Hg-sec.
Animals↗
Development of a method to measure kinetics of radiolabelled monoclonal antibody in human tumour with applications to microdosimetry: positron emission tomography studies of iodine-124 labelled 3F8 monoclonal antibody in glioma.
We present a method to assess quantitatively the immunological characteristics of tumours using radiolabelled monoclonal antibody and positron emission tomography (PET) to improve dosimetry for radioimmunotherapy. This method is illustrated with a glioma patient who was injected with 96.2 MBq of iodine-124 labelled 3F8, a murine antibody (IgG3) specific against the ganglioside GD2. Serial PET scans and plasma samples were taken over 11 days. A three-compartment model was used to estimate the plasma to tumour transfer constant (K1), the tumour to plasma transfer constant k2, the association and dissociation constants (k3, k4) of antibody binding, and the binding potential. Tumour radioactivity peaked at 18 h at 0.0045% ID/g. The kinetic parameters were estimated to be: K1 = 0.048 ml h-1 g-1, k2 = 0.16 h-1, k3 = 0.03 h-1, k4 = 0.015 h-1 and BP = 2.25. Based on these kinetic parameters, the amount of tumour-bound radiolabelled monoclonal antibody was calculated. This method permits estimates of both macrodosimetry and microdosimetry at the cellular level based on in vivo non-invasive measurement.
Brain↗
Treatment of spinal epidural neuroblastoma xenografts in rats using anti-GD2 monoclonal antibody 3F8.
Epidural neuroblastoma xenografts in nude rats causing paraparesis were treated with intravenous injection of an anti-GD2 monoclonal antibody 3F8. Metastatic or primary epidural tumors in humans cause rapid neurologic compromise. Treatment is often unsatisfactory. An animal model was established to study antibody targeted therapy of epidural tumor. Human neuroblastoma was xenotransplanted into the thoracic epidural space of nude rats. When paraparesis developed, animals were treated intravenously with an anti-GD2 monoclonal antibody, 3F8, either alone or radiolabeled with 131Iodine. Improvement in neurologic function occurred in 2 of 20 (10%) animals receiving no treatment or control antibody, 14 of 17 (82%) animals receiving 3F8 alone and all 9 animals receiving 131I-3F8 (p < 0.0001 for 3F8 or 131I-3F8 vs. control). Six animals treated with 3F8 alone recovered normal neurologic function and remained well until sacrifice 10 days later. Four animals treated with 3F8 alone had no tumor evident on pathologic examination. The percent injected dose of 131I-3F8/g tumor in 5 samples ranged from 0.73% to 3.8%. These observations demonstrate that neoplastic epidural compression of the spinal cord in the rat can be treated successfully with intravenous unmodified monoclonal antibody and that signs of neurologic dysfunction can be reversed. The potential of this approach in treating patients with epidural tumors and other neoplasms, especially those that are not sensitive to chemotherapy or radiotherapy, deserves to be explored.
Animals↗
Hiatal hernia on whole-body radioiodine survey mimicking metastatic thyroid cancer.
Total body I-131 scanning done on a 67-year-old woman with thyroid cancer revealed abnormal tracer uptake within the mid-thorax, thought to represent metastasis in the mediastinum or thoracic spine. Single-photon emission computed tomography images of the thorax showed contiguity between the thoracic uptake and the normal, physiologic uptake of radioiodine in the stomach, suggesting physiologic accumulation within a hiatal hernia. To confirm the alimentary tract location of the radioiodine, a study using orally administered Tc-99m SC in water was performed. The images were similar to the iodine images and revealed a pattern consistent with hiatal hernia. A hiatal hernia was also observed as an incidental finding on chest radiographs and an MRI. This case illustrates the potential for an abnormal anatomic configuration to mimic metastatic thyroid cancer and shows how SPECT and oral Tc-99m SC images may be useful in making this distinction.
Aged↗
Phase I dose-escalation trial of iodine 131-labeled monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma.
PURPOSE: Eighteen patients with recurrent or refractory CD21-positive, non-Hodgkin's lymphoma (NHL) were treated in a phase IA dose-escalation therapeutic trial of iodine 131 labeled to a fixed dose of OKB7. METHODS: Individual doses of 30 to 50 mCi of 131I on 25 mg OKB7 were administered 2 to 3 days apart to achieve four total 131I-OKB7 dose levels of 90, 120, 160, and 200 mCi. Pharmacology, dosimetry, therapeutic effects, toxicity, human anti-mouse antibody (HAMA) response, and maximum-tolerated dose (MTD) were determined. Patients were evaluated by imaging studies (including whole-body gamma camera or single-photon emission computed tomography [SPECT] scans), flow cytometric analysis, bone marrow biopsy, and serial blood sampling. RESULTS: Median plasma and whole-body half-lives (T1/2) were 16 hours and 14 hours, respectively. Plasma and whole-body radiation doses were 0.0081 Gy/mCi and 0.0022 Gy/mCi, respectively. Specific tumor visualization was noted in eight of 18 patients. HAMA was detected in 12 of 16 patients. Nonhematologic toxicity was limited to asymptomatic elevations of thyroid-stimulating hormone (TSH) in five of 15 patients. Hematologic toxicity was observed in six of 18 patients, but was severe in only two patients. MTD in patients with diffuse lymphomatous bone marrow involvement was determined to be 200 mCi in four divided doses of 50 mCi 131I/25 mg OKB7. Antitumor activity was observed in 13 of 18 patients (one partial response [PR] and 12 mixed responses) and was dependent on the 131I-OKB7 dose administered. In general, palpable peripheral lymphadenopathy, enlarged spleens, skin lesions, and circulating OKB7-positive peripheral lymphocytes responded most readily to treatment. 131I-OKB7 was safely administered to a patient in leukemic phase of NHL with prompt subsequent loss of approximately 1 kg of tumor cells from the peripheral blood without associated tumor lysis syndrome. CONCLUSION: Because antitumor activity with tolerable toxicity was observed in the majority of this group of heavily pretreated patients, phase II investigation of mAb OKB7 radioconjugates in the therapy of NHL is warranted.
Adult↗
Antibody localization in human renal cell carcinoma: a phase I study of monoclonal antibody G250.
PURPOSE: To define the imaging and biodistribution characteristics of iodine 131-labeled monoclonal antibody (mAb) G250 (131I-mAbG250), which recognizes a cell-surface antigen expressed by human renal cell carcinoma (RCC). PATIENTS AND METHODS: G250 is a cell-surface antigen recognized by mAbG250 expressed by RCC but not detected in normal kidney. Clear-cell RCC, the most frequent form of RCC, shows homogeneous expression of G250, whereas non-clear-cell RCC and cancers derived from other organs generally do not express G250. Expression in normal tissues is highly restricted and limited to large bile ducts and gastric epithelium. 131I-mAbG250 was administered intravenously (IV) to 16 patients with RCC 7 to 8 days before surgery at five dose levels, with at least three patients entered at each dose level. RESULTS: Clear tumor images were observed in 12 patients with G250-positive tumors and in one of three patients with G250-negative tumors. Imaged lesions in the peritoneal cavity were confirmed at surgery. The smallest lesion visualized was 8 mm in diameter. The specificity of 131I-mAbG250 localization to tumor tissue was established by radioactivity measurements, autoradiography, and immunohistochemistry of biopsied tissues, and technetium 99-human serum albumin blood-flow studies. The fraction of the injected 131I-mAbG250 dose per gram tumor (%ID/g tumor) localized in G250-positive tumors showed a broad range, but reached levels as high as 0.02% to 0.12%. CONCLUSION: 131I-mAbG250 localized specifically to G250 antigen-positive RCC and seems to have considerable potential as an imaging agent in RCC patients. 131I-mAbG250 uptake in the tumors, relative as well as absolute, are among the highest reported for tumor biopsies obtained 8 days after IV mAb administration. Based on the specific localization and high accumulation, mAb G250 may have therapeutic potential.
Adult↗
Recent achievements in the development of radiolabeled monoclonal antibodies for diagnosis, therapy and biologic characterization of human tumors.
Human tumors express antigenic sites that can serve as targets for radiolabeled monoclonal antibodies for diagnosis, therapy and biologic characterization of human tumors in vivo. Over the last decade, nearly 200 clinical trials have been performed which demonstrate that tumors can be detected with excellent sensitivity and specificity. Tumors which are otherwise occult, particularly for colorectal (anti-CEA and anti-TAG-72 antibodies) and ovarian cancer (anti-TAG-72 and anti-HMFG), are detected in a significant fraction of problem patients. Therapy using radiolabeled antibodies has been effective in lymphomas, leukemias and neuroblastomas, and is beginning to show promise in other solid tumors. Biologic characterization of tumors is likely to become more and more important in the future as monoclonal antibodies against oncogene products, such as her-2-neu, are developed. Development of new antibody forms through genetic engineering techniques, and the continual evolution toward higher resolution imaging instruments, such as PET and SPECT, will lead to further clinical improvements in cancer detection.
Antibodies, Monoclonal↗
A model for others: a strategy for improving diagnosis and therapy of human malignancies using monoclonal antibodies targeting TAG-72 oncofetal antigen.
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Antigens, Neoplasm↗
Tumor imaging and therapy.
Oncology applications in nuclear medicine include both the staging of tumors, e.g., bone scanning, and monitoring response to therapy with tumor-specific radionuclides such as 67Ga-citrate and 201Tl-chloride. An increasing role for positron emission tomography and monoclonal antibody studies in oncology is emerging, and therapeutic applications in thyroid cancer and in the treatment of metastatic bone pain are achieving impressive results. This area is likely to become the fastest growing component of nuclear medicine practice over the next decade.
Humans↗
Three-dimensional dosimetry for radioimmunotherapy treatment planning.
Absorbed-dose calculations for radioimmunotherapy are generally based on tracer imaging studies of the labeled antibody. Such calculations yield estimates of the average dose to normal and target tissues assuming idealized geometries for both the radioactivity source volume and the target volume. This work describes a methodology that integrates functional information obtained from SPECT or PET with anatomical information from CT or MRI. These imaging modalities are used to define the actual shape and position of the radioactivity source volume relative to the patient's anatomy. This information is then used to calculate the spatially varying absorbed dose, depicted in "colorwash" superimposed on the anatomical imaging study. By accounting for individual uptake characteristics of a particular tumor and/or normal tissue volume and superimposing resulting absorbed-dose distribution over patient anatomy, this approach provides a patient-specific assessment of the target-to-surrounding normal tissue absorbed-dose ratio. Such information is particularly important in a treatment planning approach to radioimmunotherapy, wherein a therapeutic administration of antibody is preceded by a tracer imaging study to assess therapeutic benefit.
Brain Neoplasms↗
Lesion-by-lesion comparison of computerized tomography and indium-111-labeled monoclonal antibody C110 radioimmunoscintigraphy in colorectal carcinoma: a multicenter trial.
C110 is an anti-carcinoembryonic antigen murine IgG1 monoclonal antibody. Indium-111-labeled C110 radioimmunoscintigraphy (RIS) in colorectal cancer was studied in 51 presurgical patients at four institutions. Planar and SPECT images were obtained at least twice between 48 and 96 hr after injection of 5 mCi/5 mg of 111In-C110. Fifty-one patients had 87 biopsy-proven lesions at surgery (57 hepatic, 30 extra-hepatic). Thirty-three patients (64.7%) had positive radionuclide scans, while 32 (62.8%) had positive CT scans (p = NS). While CT was better at overall lesion detection (62.1% versus 56%, p < 0.05), radionuclide scans were better than CT for extra-hepatic disease (60% versus 46.7%, p < 0.01). Hepatic metastases (52.6%) were visualized by Mab scans to selectively concentrate radioactivity. Uptake in draining lymph nodes was a significant limitation, making evaluation of these sites difficult. Indium-111-C110 shows selective uptake in metastatic colorectal cancer, including more than half of all hepatic lesions evaluated.
Adult↗
Modeling and dosimetry of monoclonal antibody M195 (anti-CD33) in acute myelogenous leukemia.
Individual patient response to radioimmunotherapy is influenced by each patient's tumor burden, antibody clearance kinetics and the antibody-antigen interaction. In hematologic malignancies, wherein antibody access to tumor-cell associated antigen is rapid, mathematical modeling may provide a quantitative basis for assessing the impact of patient variability on a particular therapeutic protocol. Compartmental modeling analysis of antibody pharmacokinetics from a Phase I trial of 131I-labeled monoclonal antibody, M195 (anti-CD33), was used to estimate tumor burden in cases of acute myelogenous leukemia and the absorbed dose in liver, spleen and red marrow. The suitability of a nonlinear, two-compartment model for simulating M195 distribution in leukemia patients was evaluated by comparing model predictions with patient measurements. The results demonstrate that for directly accessible, hematologically distributed tumor cells, a two-compartment model fits observed patient biodistribution data and may provide information regarding both total tumor burden and tumor burden in the liver, spleen and red marrow. The model also provides biodistribution information for absorbed dose calculations to tissues that are not directly sampled. Such information is important in determining the optimum therapeutic dose of radiolabeled antibody for a given patient.
Antibodies, Monoclonal↗
Optimizing the recovery of chemically reduced monoclonal antibody for site-specific technetium-99m radiolabeling.
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Animals↗
The correct dose: pharmacologically guided end point for anti-growth factor therapy.
Strategies to block the effects of tumor growth factors, such as estrogen, and to recruit other regulatory elements, such as with retinoids, have focused interest on the possibility of successful tumor intervention approaches. Approaches that neutralize the effects of critical molecules that drive tumor promotion are attractive targets for evaluation as new intervention agents. Clinical intervention trials with early stage patients or with subjects from "high risk" populations impose stricter types of constraints than conventional chemotherapy approaches in advanced stage patients. The potential for short-term toxicity has to be considered, as it may affect subject accrual or compliance. The longer expected survival of intervention subjects mandates closer attention to the possibilities of unexpected long-term toxicities with chronic administration of an intervention agent. As part of a Phase I clinical trial evaluating the utility of a monoclonal antibody directed against the autocrine growth factor, gastrin-releasing peptide to block the growth of small cell lung cancer, we developed a mathematical model to predict the requisite amount of antibody to neutralize growth factor effect. This model requires knowledge of the equilibrium concentration of the secreted growth factor, specific receptor, and bioavailability of the antibody in the tumor interstitium. A range of possible target doses of antibody can be developed to address the potential for heterogeneity frequently encountered in such systems, including a range of levels for peptide production and specific receptor expression. This approach could be applied to rationally derive treatment or intervention in which specific information regarding the relevant binding parameters is available. Through refinement of this modeling approach more context-specific dosing of agonist/antagonists could be determined which may decrease side effects associated with the drug administration.
Antibodies, Monoclonal↗
Tl-201 uptake in recurrent pigmented villonodular synovitis. Correlation with three-phase bone imaging.
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Female↗