Role of nuclear medicine in the treatment of malignant gliomas: the locoregional radioimmunotherapy approach

The high-grade malignant gliomas (anaplastic astrocytomas and glioblastoma) have a very bad prognosis since the available methods of treatment (surgery, radiotherapy and chemotherapy) are unable to control the progression of the disease for long. The use of specific monoclonal antibodies labelled with a suitable isotope (iodine-131 or yttrium-90) represents an effective approach to hamper tumour regrowth. Some authors have injected the antibodies intravenously, or have tried to increase the tumour/background ratio with the avidin/ biotin system. In many cases the labelled monoclonal antibodies were injected directly into the tumoral bed after the operation. The authors’ experiences concern a quite large locoregional radioimmunotherapy study which was performed by using antitenascin antibodies labelled initially with ¹³¹I and more recently with ⁹⁰Y. The clinical results demonstrate the ability of this technique to control, for a long time, the growth of these tumours. The glioblastoma median survival was prolonged to 25 months (¹³¹I group) or 31 months (⁹⁰Y group). The response rate (which comprises PR, CR and NED) was 47.1% (glioblastoma ¹³¹I group) or 40% ( glioblastoma ⁹⁰Y group). In many cases a significant tumour shrinking effect was radiologically demonstrated. The use of ⁹⁰Y proved more favourable in bulky lesions, and reduced the radioprotection problems.     

Gamma camera emission tomography using radiolabelled antibodies

Single photon emission computed tomography (SPECT) of 52 patients injected with 131I and 111In labelled monoclonal antibodies has been undertaken. Patients with tumours within the thorax or lower abdomen were imaged 48-72 h following administration of 80 MBq 131I or 111In labelled monoclonal antibody. Tumour detection from the reconstructed views was compared with that from the planar images. Studies of patients injected with 131I labelled antibodies required long data collection times otherwise image quality was unsatisfactory. Emission tomography using 111In labelled antibodies provided high quality reconstructed images using data collection times acceptable for most patients, and tumour deposits not confidently detected on planar images were clearly visualised in the axial views. These studies demonstrate the potential of radiolabelled antibody emission tomography.     

Gamma camera emission tomography using radiolabelled antibodies

Single photon emission computed tomography (SPECT) of 52 patients injected with ¹³¹I and ¹¹¹In labelled monoclonal antibodies has been undertaken. Patients with tumors within the thorax or lower abdomen were imaged 48–72h following administration of 80 MBq ¹³¹I or ¹¹¹In labelled monoclonal antibody. Tumour detection from the reconstructed views was compared with that from the planar images. Studies of patients injected with ¹³¹I labelled antibodies required long data collection times otherwise image quality was unsatisfactory. Emission tomography using ¹¹¹In labelled antibodies, provided high quality reconstructed images using data collection times acceptable for most patients, and tumour deposits not confidently detected on planar images were clearly visualised in the axial views. These studies demonstrate the potential of radiolabelled antibody emission tomography.     

Differences in tumour and normal tissue concentrations of iodine- and indium-labelled monoclonal antibody. II. Biodistribution studies in mice with human tumour xenografts

The blood, tumour and whole-body levels and survivals of 131I- and 111In-labelled monoclonal antibody (791T/36) have been compared in mice with human tumour xenografts. The blood levels and survivals of 131I- and 111In-labelled antibody were similar when expressed as proportions of the injected doses. However, the whole-body survival of 111In following administration of 111In-labelled antibody was over twice as long as that of 131I after administration of 131I-labelled antibody, principally because free 131I was rapidly excreted but free 111In was retained, primarily in liver, spleen and kidneys. Consequently, when expressed in relation to the whole body, blood levels of 111In became progressively lower than those of 131I following administration of labelled antibodies. In mice with human tumour xenografts the proportion of the injected dose of 111In from 111In-labelled antibody deposited in tumour tissue was 4-5 times higher than that of 131I from 131I-labelled antibody. When compared with the whole-body levels of radiolabel the difference was less marked, although 111In accumulation in tumour was more rapid. The higher levels and longer retention of 111In in tumour produced tumour-to-blood ratios that were 7-8 times those achieved with 131I-labelled antibody.     

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with 131I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using 131I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.     

Radiolabelled monoclonal antibodies against alpha-fetoprotein for in vivo localization of human hepatocellular carcinoma by immunotomoscintigraphy

Two high affinity monoclonal antibodies, designated AF01 and AF04, directed against distinct epitopes of human alpha-fetoprotein (AFP) and the Fab fragments of one of them, were labelled with ¹³¹I and injected into 18 patients with AFP producing hepatocellular carcinoma (HCC) in order to carry out imaging studies by tomoscintigraphy. Twelve patients were injected with whole antibody, only three of seven patients injected with AF01 and two of five patients injected with AF04 had a positive scan. In contrast, five out of six patients injected with labelled Fab fragments of AF04 had positive imaging. These results confirm that tumour imaging of HCC using ¹³¹I labelled monoclonal antibody against AFP is feasible. Moreover, utilization of tomoscintigraphy in place of linear scintigraphy and Fab fragments instead of whole immunoglobulin may improve the sensitivity of radioimmunolocalization. This technique provides useful information on the in vivo distribution of monoclonal antibodies directed against AFP and on the practicability of the eventual therapeutic use of anti-AFP antibodies in HCC.This work was supported by Grant number 84D16 from the Institut Gustave-Roussy     

Therapeutic advantages of Auger electron- over beta-emitting radiometals or radioiodine when conjugated to internalizing antibodies

Recent studies suggest a higher anti-tumour efficacy of internalizing monoclonal antibodies (MAbs) when labelled with Auger electron emitters, as compared with beta-emitters. The aim of this study was to compare the anti-tumour efficacy and toxicity of the internalizing MAb, CO17-1A, labelled with Auger electron emitters (125I, (111)In) versus conventional beta(-)-emitters (131I, 90Y) in a colon cancer model, and to assess whether the residualizing radiometals may have therapeutic advantages over the conventionally iodinated conjugates. Biodistribution studies of 125I-, (111)In- or 88Y-labelled CO17-1A were performed in nude mice bearing subcutaneous human colon cancer xenografts. For therapy, the mice were injected with either unlabelled or 125I-, 131I-, (111)In- or 90Y-labelled CO17-1A IgG2a, whereas control groups were left untreated or were given a radiolabelled isotype-matched irrelevant antibody. The influence of internalization was assessed by comparing the results with those obtained with an anti-carcinoembryonic antigen (CEA) antibody which does not internalize to a relevant extent. The maximum tolerated activities (MTA) and doses (MTD) of each agent were determined. Myelotoxicity and potential second-organ toxicities, as well as tumour growth, were monitored. Bone marrow transplantation (BMT) was performed in order to enable dose intensification. Radiometals showed significantly better tumour-to-blood ratios than the respective iodinated conjugates. The MTAs of 131I- and 125I-CO17-1A without artificial support were 11.1 MBq (300 microCi) and 111 MBq (3 mCi), respectively; the MTA of the metals was reached at 4 MBq (100 microCi) for 90Y-, and at 85 MBq (2.3 mCi) for (111)In-CO17-1A. Myelotoxicity was dose limiting in all cases. BMT enabled an increase in the MTA to 15 MBq (400 microCi) of 131I-labelled CO17-1A, to 4.4 MBq (120 microCi) of 90Y-labelled CO17-1A, and to 118 MBq (3.2 mCi) of (111)In-labelled CO17-1A, while the MTA of 125I-CO17-1A had not been reached at 185 MBq (5 mCi) with BMT. Whereas no significant therapeutic effects were seen with unlabelled CO17-1A, tumour growth was retarded significantly with its radiolabelled forms. The therapeutic results were significantly (P<0.01) better with both Auger electron emitters (125I and (111)In) than with the beta-emitters, and, in accordance with the biodistribution data, a trend towards better therapeutic results was found with radiometals (more complete remissions) as compared with radioiodine. In contrast, at equitoxic doses, no significant difference was observed in the therapeutic efficacy of 131I- versus 125I-labelled non-internalizing anti-CEA antibody, F023C5. These data suggest that, at equitoxic doses, the therapeutic efficacy of internalizing MAbs labelled with Auger electron emitters, such as 125I or (111)In, is superior to that of internalizing MAbs labelled with conventional beta-emitters. The lower toxicity of Auger electron emitters may be due to the short path length of their low-energy electrons, which can reach the nuclear DNA only if the antibody is internalized (as is the case in antigen-expressing tumour tissue, but not in the stem cells of the red marrow).     

Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour

Purpose : Estimating the absorbed dose to tumour relative to normal tissues has often been used in the assessment of the therapeutic efficacy of radiolabelled antibodies for radioimmunotherapy. Typically, the calculations assume a uniform dose deposition and response throughout the tumour. However, the heterogeneity of the dose delivery and response within tumours can lead to a radiobiological effect inconsistent with dose estimates. The aim was to assess the influence of antibody and radionuclide characteristics on the heterogeneity of dose deposition. Materials and methods : Quantitative images of the temporal and spatial heterogeneity of a range of antibodies in tumour were acquired using radioluminography. Subsequent registration with images of tumour morphology then allowed the delineation of viable and necrotic areas of tumour and the measurement of the antibody concentration in each area. A tumour dosimetry model then estimated the absorbed dose from 131 I and 90 Y in each area. Results : Tumour-specific antibodies initially localized in the viable radiosensitive areas of tumour and then penetrated further into tumour with continued tumour accretion. Multivalent antibodies were retained longer and at higher concentrations in viable areas, while monovalent antibodies had greater mobility. In contrast, non-specific antibodies penetrated into necrotic regions regardless of their size. As a result, multivalent, specific antibodies delivered a significantly larger dose to viable cells compared with monovalent antibodies, while non-specific antibodies deposited most of the dose in necrotic areas. There was a significant difference in dose estimates when assuming a unifrom dose deposition and accounting for heterogeneity. The dose to the viable and necrotic areas also depended on the properties of the radionuclide where antibodies labelled with 131 I generally delivered a higher dose throughout the tumour even though the instantaneous dose-rate distribution for 90 Y was more uniform. Conclusions : The extent of heterogeneity of dose deposition in tumour is highly dependent on the antibody characteristics and radionuclide properties, and can enhance therapeutic efficacy through the selective dose delivery to the radiosensitive areas of tumour.     

Antibody and radionuclide characteristics and the enhancement of the effectiveness of radioimmunotherapy by selective dose delivery to radiosensitive areas of tumour

PURPOSE: Estimating the absorbed dose to tumour relative to normal tissues has often been used in the assessment of the therapeutic efficacy of radiolabelled antibodies for radioimmunotherapy. Typically, the calculations assume a uniform dose deposition and response throughout the tumour. However, the heterogeneity of the dose delivery and response within tumours can lead to a radiobiological effect inconsistent with dose estimates. The aim was to assess the influence of antibody and radionuclide characteristics on the heterogeneity of dose deposition. MATERIALS AND METHODS: Quantitative images of the temporal and spatial heterogeneity of a range of antibodies in tumour were acquired using radioluminography. Subsequent registration with images of tumour morphology then allowed the delineation of viable and necrotic areas of tumour and the measurement of the antibody concentration in each area. A tumour dosimetry model then estimated the absorbed dose from 131I and 90Y in each area. RESULTS: Tumour-specific antibodies initially localized in the viable radiosensitive areas of tumour and then penetrated further into tumour with continued tumour accretion. Multivalent antibodies were retained longer and at higher concentrations in viable areas, while monovalent antibodies had greater mobility. In contrast, non-specific antibodies penetrated into necrotic regions regardless of their size. As a result, multivalent, specific antibodies delivered a significantly larger dose to viable cells compared with monovalent antibodies, while non-specific antibodies deposited most of the dose in necrotic areas. There was a significant difference in dose estimates when assuming a uniform dose deposition and accounting for heterogeneity. The dose to the viable and necrotic areas also depended on the properties of the radionuclide where antibodies labelled with 131I generally delivered a higher dose throughout the tumour even though the instantaneous dose-rate distribution for 90Y was more uniform. CONCLUSIONS: The extent of heterogeneity of dose deposition in tumour is highly dependent on the antibody characteristics and radionuclide properties, and can enhance therapeutic efficacy through the selective dose delivery to the radiosensitive areas of tumour.     

Limitations to the killing of tumours using radiolabelled antibodies

We have calculated the minimum requirements for effective therapy using intravenously administered, tumour-directed antibodies labelled with either iodine 131 or yttrium 90. A lethally large amount of either radionuclide would be required to achieve tumour destruction. At least a 10-fold increase in tumour uptake is necessary to combine tumour destruction with a survivable whole-body dose. The required improvement in specific uptake can be substantially reduced by accelerating the excretion of radioactivity outside the tumour. For all situations studied, yttrium 90 is superior to iodine 131 as a cytotoxic label.     

Immunoscintigraphy of experimental transplantable tumours using monoclonal antibody against myelin basic protein.

Monoclonal antibody was prepared against myelin basic protein a so-called pancarcinoma antigen. After labelling with 131I the monoclonal antibody was injected into Lewis-lung cancer mice and rats with Walker breast cancer. Two, 24, 48, 72 and 96 hours after the labelled monoclonal antibody injection, radioimmunoimaging studies were carried out. After each gamma-camera study, organ distribution of the labelled monoclonal antibody was determined with radiobioassay technique which showed significantly higher activity in the tumour tissue than in healthy ones. Significant sample radioactivity could be recovered in the tumour masses 48 hours after injection, which persisted even after 96 hours. The later finding might enable diagnosing types of malignancy with isotope-labelled monoclonal antibody against myelin basic protein.     

Antibody-guided three-step therapy for high grade glioma with yttrium-90 biotin

While the incidence of brain tumours seems to be increasing, median survival in patients with glioblastoma remains less than 1 year, despite improved diagnostic imaging and neurosurgical techniques, and innovations in treatment. We have developed an avidin-biotin pre-targeting approach for delivering therapeutic radionuclides to gliomas, using anti-tenascin monoclonal antibodies, which seems potentially effective for treating these tumours. We treated 48 eligible patients with histologically confirmed grade III or IV glioma and documented residual disease or recurrence after conventional treatment. Three-step radionuclide therapy was performed by intravenous administration of 35 mg/m2 of biotinylated anti-tenascin monoclonal antibody (1st step), followed 36 h later by 30 mg of avidin and 50 mg of streptavidin (2nd step), and 18-24 h later by 1-2 mg of yttrium-90-labelled biotin (3rd step). 90Y doses of 2.22-2.96 GBq/m2 were administered; maximum tolerated dose (MTD) was determined at 2.96 GBq/m2. Tumour mass reduction (>25%-100%), documented by computed tomography or magnetic resonance imaging, occurred in 12/48 patients (25%), with 8/48 having a duration of response of at least 12 months. At present, 12 patients are still in remission, comprising four with a complete response, two with a parital response, two with a minor response and four with stable disease. Median survival from 90Y treatment is 11 months for grade IV glioblastoma and 19 months for grade III anaplastic gliomas. Avidin-biotin based three-step radionuclide therapy is well tolerated at the dose of 2.2 GBq/m2, allowing the injection of 90Y-biotin without bone marrow transplantation. This new approach interferes with the progression of high-grade glioma and may produce tumour regression in patients no longer responsive to other therapies.     

A comparison of iodine and indium labelled anti CEA intact antibody, F(ab)2 and Fab fragments by imaging tumour xenografts

An intact anti CEA monoclonal antibody (C198) and its F(ab)2 and Fab fragments have been radiolabelled with 131I and 111In and their biodistributions and tumour imaging capabilities examined in mice with human tumour xenografts. 131I labelled F(ab)2 and Fab fragments showed improved tumour visualization compared with intact antibody, principally because of the more rapid whole body elimination of the radiolabel. Studies using 111In labelled fragments demonstrated that a major proportion (greater than 60%) of the administered radioactivity was retained in the kidneys and this was detrimental to tumour imaging in the mouse xenograft model. The present study emphasizes the importance of selecting the most appropriate combination of antibody preparation and radiolabel, and that the choice of radionuclide is influenced by both its physical and subsequent pharmacological characteristics.     

Detection of thyroid tumour using a monoclonal 123I anti-human thyroglobulin antibody

A monoclonal antibody to human thyroglobulin was radiolabelled with 123I NaI and shown to be a stable and biologically active reagent in vivo. When injected intravenously into 12 patients with cancer of the thyroid on thyroxine-replacement therapy, 6 of the 12 patients had localization of the labelled antibody in tumour sites. These results were compared to 131I scans done on the same patients 1 month after stopping thyroxine. The biological half-life of the antibody in the blood was influenced by the levels of circulating thyroglobulin.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma.

In the past decade, several new antibody-based therapies - using either radiolabelled or unlabelled monoclonal antibodies - have become available for the treatment of patients with refractory or recurrent non-Hodgkin's lymphoma (NHL). Unlabelled monoclonal antibodies (mAbs) kill lymphoma cells by activating host immune effector mechanisms, or by inducing apoptosis. These mAbs can also be used to guide radionuclides to the lymphoma. This radioimmunotherapy (RIT) has been studied with various nuclides (131I, 90Y, 67Cu and 186Re) and with various mAbs. In this review the radionuclides, methods of dosing and recent RIT studies in patients with B-cell NHL are reviewed. Most of these studies demonstrate that RIT is an effective new treatment modality for NHL.     

Therapeutic potential of 90Y- and 131I-labeled anti-CD20 monoclonal antibody in treating non-Hodgkin's lymphoma with pulmonary involvement: a Monte Carlo-based dosimetric analysis.

Pulmonary involvement is common in patients with non-Hodgkin's lymphoma (NHL). (90)Y- and (131)I-anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab, respectively) have been approved for the treatment of refractory low-grade follicular NHL. In this work, we used Monte Carlo-based dosimetry to compare the potential of (90)Y and (131)I, based purely on their emission properties, in targeted therapy for NHL lung metastases of various nodule sizes and tumor burdens. METHODS: Lung metastases were simulated as spheres, with radii ranging from 0.2 to 5.0 cm, which were randomly distributed in a voxelized adult male lung phantom. Total tumor burden was varied from 0.2 to 1,641 g. Tumor uptake and retention kinetics of the 2 radionuclides were assumed equivalent; a uniform distribution of activity within tumors was assumed. Absorbed dose to tumors and lung parenchyma per unit activity in lung tumors was calculated by a Monte Carlo-based system using the MCNP4B package. Therapeutic efficacy was defined as the ratio of mean absorbed dose in the tumor to that in normal lung. Dosimetric analysis was also performed for a lung-surface distribution of tumor nodules mimicking pleural metastatic disease. RESULTS: The therapeutic efficacy of both (90)Y and (131)I declined with increasing tumor burden. In treating tumors with radii less than 2.0 cm, (131)I targeting was more efficacious than (90)Y targeting. (90)Y yielded a broader distribution of tumor absorbed doses, with the minimum 54.1% lower than the average dose; for (131)I, the minimum absorbed dose was 33.3% lower than the average. The absorbed dose to normal lungs was reduced when the tumors were distributed on the lung surface. For surface tumors, the reductions in normal-lung absorbed dose were greater for (90)Y than for (131)I, but (131)I continued to provide a greater therapeutic ratio across different tumor burdens and sizes. CONCLUSION: Monte Carlo-based dosimetry was performed to compare the therapeutic potential of (90)Y and (131)I targeting of lung metastases in NHL patients. (131)I provided a therapeutic advantage over (90)Y, especially in tumors with radii less than 2.0 cm and at lower tumor burdens. For both (90)Y- and (131)I-labeled antibodies, treatment is more efficacious when applied to metastatic NHL cases with lower tumor burdens. (131)I has advantages over (90)Y in treating smaller lung metastases.     

Monoclonal antibodies: old and new trends in breast cancer imaging and therapeutic approach

Over the last two decades, various research protocols were applied for scintigraphic imaging, prognosis and treatment of breast cancer, using monoclonal antibodies. Monoclonal antibodies approved by the United States Food and Drug Administration (FDA) include the anti-carcinoembryonic antigen (CEA), and B72.3, prepared against the tumour-associated glycoprotein, TAG-72. The recombinant humanized "cold" anti-HER2 monoclonal antibody (trastuzumab), which targets oncogene receptor HER2 has hitherto been the only monoclonal antibody widely used for the treatment of breast cancer in the USA, with or without chemotherapy. Trastuzumab is constructed against the HER2 oncogene receptor (also known as neu or c-erb-B2), which is overexpressed in 25%-30% of breast cancer cell lines and is associated with poor prognosis. Immuno-lymphoscintigraphy is also applied to guide and monitor the effect of treatment regimes. Radiolabelled, "hot" monoclonal antibodies are currently being applied for the treatment of primary or metastatic breast cancer, in experimental, pre-clinical, or clinical trials, in combination with traditional external beam radiotherapy and/or chemotherapy. Radioimmunotherapy comprises systemically administered monoclonal antibodies, linked to high-energy, beta-emitting radionuclides. Radioactive antibodies, in the form of yttrium-90 (90Y)-BrE-3, 90Y- m170 and 131I- or 90Y- labelled L6 antibody, are applied with adjuvant autologous peripheral blood stem cells transfusion, to prevent myelotoxicity. Partial or rarely complete responses to "hot" antibody treatment, of breast cancer have been reported. Innovative strategies using this combined-modality treatment hold promise for better disease-free and survival rates.     

A comparison of iodine and indium labelled anti CEA intact antibody,F(ab)2 and Fab fragments by imaging tumour xenografts

An intact anti CEA monoclonal antibody (C198) and its F(ab)₂ and Fab fragments have been radiolabelled with¹³¹I and¹¹¹In and their biodistributions and tumour imaging capabilities examined in mice with human tumour xenografts.¹³¹I labelled F(ab)₂ and Fab fragments showed improved tumour visualization compared with intact antibody, principally because of the more rapid whole body elimination of the radiolabel. Studies using¹¹¹In labelled fragments demonstrated that a major proportion (>60%) of the administered radioactivity was retained in the kidneys and this was detrimental to tumour imaging in the mouse xenograft model. The present study emphasizes the importance of selecting the most appropriate combination of antibody preparation and radiolabel, and that the choice of radionuclide is influenced by both its physical and subsequent pharmacological characteristics.