Introduction to the Seventh Conference on Radioimmunodetection and Radioimmunodetection and Radioimmunotherapy of Cancer.
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Humans↗
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Radioimmunodetection of colorectal carcinoma using technetium-99m-labeled Fab' fragments of the IMMU-4 anti-carcinoembryonic antigen monoclonal antibody.
BACKGROUND: Radioimmunodetection of cancer using monoclonal antibody fragments offers certain potential advantages over that with whole monoclonal antibodies, including the ability to image early (i.e., to provide images at an early time after injection of the radioantibody) while minimizing the incidence of human anti-mouse antibody response. This paper reports a prospective trial comparing radioimmunodetection with IMMU-4 (a murine anti-CEA monoclonal antibody) 99mTc-labeled Fab' fragments to conventional imaging in 35 colorectal cancer patients. METHODS: All patients were investigated by conventional diagnostic methods (CDM) within 4 weeks of radioimmunodetection. Surgical corroboration of findings was obtained in 26 patients (15 with evidence of disease on CDM [CDM+] and 11 with abnormal serum CEA [CDM-] as the only evidence for recurrence). After 1 mg IMMU-4 99mTc-Fab' was injected (19.3 mCi on average), patients underwent planar/SPECT radioimmunodetection 2-5 hours later and planar radioimmunodetection 18-24 hours later. Three patients underwent a second radioimmunodetection study 16, 20 and 23 months after the first. RESULTS: Radioimmunodetection was superior to CDM, accurately predicting disease distribution in six nonsurgical and ten CDM+ surgical patients, and was complementary to computed tomography in two nonsurgical and two CDM+ surgical patients. Radioimmunodetection would have directed or changed management decisions in 6 of the 15 (40%) CDM+ surgical patients. Radioimmunodetection correctly identified all recurrent tumor in 8 of 11 CDM- surgical patients and was negative in one patient with cirrhosis and no recurrence, representing a potential clinical benefit of 82%. Analyzed on a regional basis, radioimmunodetection was found to be superior to CDM in extrahepatic abdomen and pelvis imaging and was complementary to (although not as accurate as) CDM in the liver. Human anti-mouse antibody did not develop in any of the patients, including three who were injected twice. CONCLUSIONS: IMMU-4 99mTc-Fab' radioimmunodetection shows promise as a clinically useful diagnostic tool in patients with colorectal cancer, detecting disease often missed by conventional imaging. IMMU-4 99mTc-Fab' may prove useful for serial radioimmunodetection studies, because human anti-mouse antibody response does not appear to be a problem with this radioimmunoconjugate. It also has the advantage of permitting same-day imaging.
Animals↗
Comparison of radioimmunodetection with other imaging methods in evaluating local relapses of colorectal carcinoma.
BACKGROUND: The prognosis for colorectal cancer patients is related closely to the extent of tumor at the time of diagnosis, and early detection of metastatic or recurrent disease is an important prerequisite for successful treatment. Radioimmunodetection is a relatively new technique to image colorectal cancer using radiolabelled monoclonal antibodies (MoAb). The goal of this study was to evaluate the clinical use of radioimmunodetection with the anti-carcinoembryonic antigen MoAb FO23C5, radiolabelled with 131I, in patients submitted to surgery for colorectal cancer and with suspected local recurrences. The results of radioimmunodetection were compared with those of computed tomography, ultrasonography, magnetic resonance imaging, and other diagnostic techniques (gastrointestinal x-ray, endoscopy, and, in selected cases, a surgical second look). METHODS: Fifty-nine patients with a rise in carcinoembryonic antigen serum levels or a clinical suspicion of recurrences entered the study. Scintigraphy was performed at multiple interval times (4-100 hours) after an intravenous injection of radiolabelled FO23C5 F(ab')2 fragments. RESULTS: The cumulative results showed the high sensitivity (89%), specificity (78%), and accuracy (86%) of radioimmunodetection. Of the radiologic methods, only magnetic resonance imaging had the same accuracy (86%), with lower specificity (64%) and higher sensitivity (93%). Computed tomographic scan and ultrasonography displayed the poorest accuracy (68% and 47%, respectively). CONCLUSIONS: Radioimmunodetection is an important imaging technique that can be used in clinical practice for the follow-up of the patient with colorectal carcinoma.
Antibodies, Monoclonal↗
Radioimmunodetection of primary and metastatic germ cell tumors containing alpha-fetoprotein.
Radioimmunodetection with an 131I anti-alpha-fetoprotein (alpha FP) has been performed in 5 patients with germ cell tumors. In 3 of them, 5 of 6 recognized or suspected tumor sites could be demonstrated. In 1 of these patients, a clinically non-apparent primary tumor was detected by this method. The 2 other patients had received intensive chemotherapy and had a persistent elevation of serum alpha FP, although usual paraclinical examinations were normal. In these patients, the labelled antibody scan did not show any abnormality. These results suggest that radioimmunodetection can be useful in patients with nonseminomatous gonadal and extragonadal tumors at the time of presentation. Usefulness of radioimmunodetection in the follow-up of these patients remains to be determined. Even in our limited series, radioimmunodetection was of no help on localizing the sites of alpha FP secretion in treated patients in whom other methods had also failed to recognize the site of abnormal alpha FP synthesis.
Adult↗
Clinical radioimmunodetection, 1978-1988: overview and suggestions for standardization of clinical trials.
In the last decade of radioimmunodetection studies the radiolabeled antibody preparations used have gradually changed from polyclonal antibodies labeled predominantly with 131I to monoclonal antibodies labeled with diverse radionuclides including 131I, 111In, 123I, and 99mTc. Over this period progressive improvement in tumor imaging has been observed when one compares the best examples of early studies, performed with 131I labeled heterosera, to the best of modern images, obtained with 123I, 99mTc, or 111In labeled monoclonal antibodies. Important findings in 61 clinical studies reviewed include the reports from several centers which demonstrate occult disease in patients with carcinoma of colon, melanoma, and lymphoma, and the improved sensitivity and specificity of radioimmunodetection in comparison to transmission computerized tomography in the lymph nodes and abdomen, in lymphoma and colon cancer, and ovarian cancer. Evaluation of the liver remains a difficult problem with this technique and standard approaches are superior in most reports. The general principle of targeting radioactivity to tumor with radiolabeled antitumor antibody and the feasibility of developing practical clinical methodology which will add new diagnostic information have clearly been established. Toxicity, particularly for index studies, is reassuringly limited. In all the studies with surgical confirmation after i.v. injection, uptake in tumor is in the range of 0.005% injected dose/g tumor, and this low tumor uptake remains the single greatest limitation of the method. A second important problem is the prompt development of human anti-mouse antibody, which reduces the usefulness of follow-up studies. A serious criticism of the information currently available on radioimmunodetection is that the clinical studies reported to date vary greatly in approach and results. The vast majority of studies are early Phase I clinical trials, from which toxicity information and biodistribution data can be derived but which give limited information about impact on clinical management. Standardization in the study design is needed in order to establish the efficacy of radioimmunodetection in adequate and well controlled clinical trials.
Antibodies, Monoclonal↗
Carcinoembryonic antigen radioimmunodetection in the evaluation of colorectal cancer and in the detection of occult neoplasms.
Radioimmunodetection of colorectal cancer was evaluated in 51 patients by injecting 131I-labeled goat antibody immunoglobulin G against carcinoembryonic antigen and performing total-body photoscans with a gamma scintillation camera 24 and 48 h later. The scintigrams were then processed by computer to subtract the images of the 99mTc-serum albumin and pertechnetate administered, which reflect background and nontarget radioactivity, from the 131I-antibody scans. The results indicate that radioimmunodetection is a safe and a potentially clinically useful cancer detection method, which in this study demonstrated primary colorectal carcinomas in 10 of 12 (83%) of the patients evaluated preoperatively and between 87% (46 of 53) and 92% (49 of 53) of known metastatic tumor sites. Thus, the method's overall sensitivity (true-positive rate) was 86%-91% on a tumor-site basis. A false-negative rate of between 9% and 14% and a false-positive rate of less than 4% were found. In 11 of the 51 patients evaluated, tumor sites were detected that were not found by other clinical methods of cancer detection. These sites of tumor were then confirmed later, as much as 40 wk after radioimmunodetection was performed. It is concluded that in colorectal cancer patients, the current method of carcinoembryonic antigen radioimmunodetection can (a) contribute to the preoperative clinical staging of the patients, (b) assist in the postoperative evaluation of tumor recurrence or spread, (c) complement other methods used to assess tumor response to therapy, (d) support the indication of a rising carcinoembryonic antigen titer (when other methods cannot detect tumor) for second-look surgery, and (e) confirm the findings of other detection measures that are less tumor-specific.
Aged↗
Imaging techniques for the radioimmunodetection of cancer.
Problems in the radioimmunodetection of cancer typically involve small lesions having low object contrast. As such, the imaging device utilized must have a high spatial resolution as well as high detection efficiency. In addition, the imaging device must be interfaced to a computer system to allow data manipulation to include background substraction, contrast enhancement, and organ subtraction techniques to be used. While the conventional scintillation camera is the most widely used imaging device in conventional nuclear medicine imaging procedures, this system does not provide adequate imaging performance for radioimmunodetection of cancer. This is true since these devices typically do not provide adequate object contrast when detecting small lesions in the presence of moderately high background activity. The Pho/Con (Searle Radiographics) is a tomographic imaging device which, when interfaced to a computer system, is capable of providing adequate lesion detection for this specialized procedure. The newest version of this tomographic imaging system has a spatial resolution and a detector efficiency which are comparable to those of the conventional scintillation camera. The system has the added advantage of relatively constant high-spatial-resolution performance as well as high sensitivity over a wide range of depths. In addition, the imaging process involves a rectilinear scanning motion which results in inherently uniform response in each plane of interest. These combined properties result in high detection of small lesions in cases where the object contrast is extremely low. These inherent imaging properties when combined with the improved contrast provided with computer manipulation of data make this system ideal for radioimmunodetection problems. In this paper, the importance of spatial resolution, count density, lesion size, and object contrast are discussed in relation to the detectability of lesions in radioimmunodetection of cancer. In addition, the characteristics of the Pho/Con and its advantages in lesion detection are described.
Computers↗
Radioimmunodetection and radioimmunotherapy of malignant melanoma. A review.
Radioimmunodetection utilizing monoclonal antibodies to various melanoma-associated surface antigens has been studied by several investigators during the past ten years. In the early trials, antibodies were labeled with 131I or 111In, but now 99mTc is almost exclusively used because of its more favorable energy for gamma camera imaging. Excellent specificity has been achieved in most studies, whereas sensitivity has been less good. In a recent European multicenter study on 493 patients sensitivity was 79% and specificity 96%. In this largest study on melanoma so far performed many previously unknown metastatic deposits were identified indicating that radioimmunodetection has a role in the management of metastatic disease. The clinical utility of immunoscintigraphy in localization of regional lymph node metastases has been documented in several investigations in recent years, indicating that this method can be used in the preoperative evaluation of patients. Radioimmunodetection has also been successfully used in the differential diagnosis of ocular lesions. However, conclusive evidence of improved patient outcome resulting from the earlier detection of melanoma lesions by immunoscintigraphy is still lacking. Anti-melanoma antibodies labeled with alpha- and beta-emitting isotopes are potential therapeutic agents, but so far there is little clinical experience with radioimmunotherapy of metastatic melanoma.
Eye Neoplasms↗
[Radioimmunodetection of human trophoblastic cancer xenograft in nude mice].
OBJECTIVE: To study the efficiency of radioimmunodetection to locate xenograft of human trophoblastic cancer in nude mouse. METHODS: Radioimmunodetection was performed with a cocktail of 131I-labeled mouse anti-hCG monoclonal antibodies to image xenogaft of human trophoblastic cancer in nude mice. Normal mouse IgG used to treat mice bearing trophoblastic cancer xenograft was used as control. Radioactivity in different tissues was measured and the tumor/non-tumor(T/NT) ratio was calculated. RESULTS: The accumulation of radioactivity in the xenograft could be recognized as early as 24 hours after the injection of the radiolabeled anti-hCG antibodies. Radioactivity accumulation became increasingly evident with time. At 72-96 hours after injection of the radiolabled antibodies, the xenograft could be clearly shown. The minimal size of the xenograft with demonstrable radioactively was 0.8 cm in diameter. The T/NT ratio increased with time and was obviously higher than that in mice treated with normal mouse IgG. CONCLUSION: Radioimmunodetection can efficiently locate human trophoblastic cancer xenograft in nude mice.
Animals↗
Radioimmunodetection of colorectal cancer.
This study examines the accuracy of colorectal cancer radioimmunodetection. Twenty-seven patients with a history of histologically-confirmed colonic or rectal carcinoma received a high-titer, purified goat anti-CEA IgG labelled with 131-I at a total dose of at least 1.0 muCi. Various body views were scanned at 24 and 48 hours after administration of the radioantibody. Three additional cases were evaluated; one had a villous adenoma in the rectum and received the 131-I-labelled anti-CEA IgG, while two colonic carcinoma patients received normal goat IgG labelled with 131-I. All of the 7 cases with primary colorectal cancer showed true-positive tumor localization, while 20 of 25 sites of metastatic colorectal cancer detected by immune scintigraphy were corroborated by other detection measures. The sensitivity of the radioimmunodetection of colorectal cancers (primary and metastatic) was found to be 90% (true-positive rate), the putative specificity (true-negative rate) was 94%, and the appraent overall accuracy of the technique was 93%. Neither the case of a villous adenoma receiving the anti-CEA IgG nor the two cases of colonic cancer receiving normal goat IgG showed tumor radiolocalization. Very high circulating CEA titers did not appear to hinder successful tumor radiolocalization. These findings suggest that in colorectal cancers the method of CEA radioimmunodetection may be of value in preoperatively determining the location and extent of disease, in assessing possible recurrence or spread postoperatively, and in localizing the source of CEA production in patients with rising or elevated CEA titers. An ancilliary benefit could be a more tumor-specific detection test for confirming the findings of other, more conventional diagnostic measures.
Antibodies, Neoplasm↗
Radioimmunodetection of cancer with radiolabeled antibodies to alpha-fetoprotein.
Sixteen patients with histologically proven malignant neoplasia were investigated by radioimmunodetection, using goat anti-alpha-fetoprotein (AFP) antibody radiolabeled with 131I. Images of the chest and abdomen were made with a scintillation camera, usually at 24 and 48 hr following injection of 1 to 2.5 mCi of radioiodinated antibody. Computer-assisted processing for the subtraction of 99mTc background radioactivity was used to enhance the detection and localization of tumors visualized by immune scintigraphy. All 12 sites involved by five AFP-producing tumors could be demonstrated by radioimmunodetection, while normal goat immunoglobulin G labeled with 131I failed to show similar results in one of the patients in whom the radioactive AFP antibody achieved tumor radiolocalization. Five patients in whom the tumors were not expected to produce AFP also had their large tumors demonstrated by immune scintigraphy in 6 of 16 tumor sites. The average tumor to non-tumor 131I image count density ratios were 3.20 and 1.96 for the AFP-containing and putatively AFP-deficient tumors, respectively. The image contrast was significantly greater for the AFP-containing tumors, and the subtraction technique enhanced the image contrast more than 2-fold. Based upon these initial results, the sensitivity of the method (true-positive rate) was 100%, its specificity (true-negative rate) was 80%, and the accuracy of the technique was 85%. This study thus indicates that radioimmunodetection of cancer with radioactive AFP antibodies can be useful in the evaluation of patients with AFP-containing neoplasms.
Adult↗
Radioimmunodetection of solid tumors. Future horizons and applications for radioimmunotherapy.
Seventeen years after the development of hybridoma technology, the clinical utility of radioimmunodetection of solid tumors using monoclonal antibody-based imaging agents has been definitively established. As expected, these first immunoscintigraphy agents demonstrate certain limitations (most notably, suboptimal tumor-to-background radiolocalization ratios and immunogenicity), suggesting that the full potential of this technology has not been realized. This article reviews research strategies for optimizing the imaging performance of radiolabeled monoclonal antibodies. Promising approaches include the development of humanized tumor-targeting vehicles, improved chelator technology to link the antibody and the radioisotope, the use of smaller immunoreactive targeting agents, modifications of the tumor or host determinants of antibody biodistribution, regional delivery of immunoscintigraphic agents, use of antibody "cocktails," and advances in image acquisition technology. The successful application of these strategies should lead to improved agents for tumor radioimmunodetection. The results of these research efforts should be useful in developing radiolabeled monoclonal antibody-based agents for solid tumor therapy.
Colonic Neoplasms↗
Overview of clinical radioimmunodetection of human tumors.
The role of radioimmunodetection in the detection of cancer has been established through the development of high affinity immunoconjugates and recent improvements in radiochemistry. Advances in imaging techniques, particularly single-photon emission computed tomography and image registration, also have dramatically improved the sensitivity and accuracy of tumor detection. Molecular engineering of immune constructs provides promise of enhanced tumor localization properties and reduced immunogenicity, allowing repeated studies to be performed. The role of radioimmunodetection in the evaluation of cancer patients will increase in importance in the future.
Adult↗
Initial clinical results with technetium-99m-labeled LL2 monoclonal antibody fragment in the radioimmunodetection of B-cell lymphomas.
BACKGROUND: Various monoclonal antibodies (MoAb) labeled with Iodine-131 or Indium-111 (In-111) have been investigated for radioimmunodetection of Hodgkin's and non-Hodgkin's lymphomas. Successful radioimmunotherapy also has been reported. The purpose of this pilot study was to stage non-Hodgkin's B-cell lymphomas (NHL) using whole body scintigraphy with technetium-99m (Tc-99m)-labeled murine monoclonal antibody LL2 (EPB-2) Fab' (Immunomedics, Morris Plains, NJ). Others have shown this MoAb to have specific binding to B-cell lymphomas by flow cytometry and immunofluorescence. Initial clinical studies by others have demonstrated targeting of NHL with the Tc-99m-labeled LL2-Fab'. METHODS: One milligram of the antibody was injected intravenously after being radiolabeled with 30 mCi Tc-99m. Fifteen patients with high (n = 6), low (n = 2), and intermediate (n = 7) grade NHL were studied. No adverse effects were noted. Planar whole body imaging and single-photon emission computed tomography were performed at 2-6 h and 20-24 h postinjection. Human anti-mouse antibody levels were determined before injection and at 2 and 6 weeks. RESULTS: In 4 of 15 patients (27%), the disease stage was altered in response to the scintigraphic findings. The physiologic biodistribution of the antibody demonstrated splenic uptake caused by antibody targeting of the white pulp and of normal B-cells, and renal uptake caused by urinary excretion. Lymph node and bone marrow involvement of known tumor sites were clearly seen. A number of previously unknown tumor sites were revealed by LL2-radioimmunodetection despite normal morphologic imaging results. Long-term follow-up of these patients is required to verify these findings. No human anti-mouse antibody elevations or adverse reactions were found in the patients studied. CONCLUSION: These preliminary data suggest that Tc-99m-labeled LL2 Fab' yields useful clinical results, especially for the staging of patients with NHL before initial therapy or for the detection of early disease recurrence.
Animals↗
Radioimmunodetection of human colon cancer in nude mice by a new monoclonal antibody A7 against human colorectal cancer.
The in vivo localization of a monoclonal antibody A7 against a human colorectal cancer was studied in nude mice bearing human solid carcinomas, to evaluate potential applications of this antibody for radioimmunodetection of cancer. The tissue distribution of 125I-labeled A7 MoAb at 3 days after i.v. injection into mice bearing five different kinds of human solid tumors revealed a high uptake ratio by colon cancer, mammary cancer, and glioblastoma. In contrast, the uptake ratio by murine colorectal cancer (Colon-38) was extremely low. In immunoscintigraphic studies, HCT-15, one of the human colon cancer, was clearly visualized with 111In-DTPA-A7 MoAb. Glioblastoma was also imaged with the same extent. These results suggest that A7 MoAb would be applicable to the in vivo radioimmunodetection of colon- and mammary-cancer, and of glioblastoma.
Adenocarcinoma↗
Radioimmunodetection of human small cell lung carcinoma xenografts in the nude rat using 111in-labelled monoclonal antibody MOC-31.
The applicability of mouse monoclonal antibody MOC-31 for in vivo radioimmunodetection of human small cell lung cancer (SCLC) was investigated in a nude rat xenograft model. MOC-31 is reactive with a 38 kD pancarcinoma membrane antigen. [111In]DTPA-MOC-31 showed good in vivo immunolocalisation to xenografted SCLC cells, whereas antigen-related uptake was low in normal rat tissues and in a control antigen-negative, human-derived tumour. Non-antigen-related uptake in the liver could be blocked by pretreatment with irrelevant antibody. It is concluded that MOC-31 can be used for radioimmunodetection of SCLC in vivo and may be suitable as a targeting device in patients.
Animals↗
Radioimmunodetection of malignant solid tumours.
An increased clinical utility of radiolabelled monoclonal antibodies (MoAb), recognizing a variety of different antigens expressed preferentially in malignant tissue, for localizing primary, metastatic and recurrent cancer has been documented in many recent investigations. This review focuses on both basic and practical aspects of radioimmunodetection in oncology and is a status report on the performance and limitations of radiolabelled antibody procedures currently applied to the clinical detection of malignant solid tumours. At this time clinically validated radioimmunodetection methods are available for colorectal, ovarian, breast, lung, thyroid medullary, and head and neck carcinoma, and melanoma. Recent advances in humanization of MoAb significantly improve the prospects of effective antibody-guided radiotherapy in the near future.
Animals↗
Potential and limitations of radioimmunodetection and radioimmunotherapy with monoclonal antibodies.
UNLABELLED: Recently, we developed a physiologically based pharmacokinetic model capable of predicting antibody biodistribution in humans by scaling up from mice. By applying this model to anticarcinoembryonic antigen murine antibody ZCE025, we address several critical issues in radioimmunodetection and radioimmunotherapy, including the optimal antibody doses, the desirable antibody form for cancer detection, the optimal combinations of antibody forms and radionuclides for cancer treatment and the effectiveness of the modality. METHODS: Under the baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used to: (a) estimate absorbed doses in tumor and normal tissues, (b) determine dose-dependent antibody uptake in the tumor, (c) simulate tumor-to-background antibody concentration ratio and (d) calculate therapeutic ratios for different antibody forms and radionuclides. Sensitivity analysis further enabled us to determine antibody delivery barriers and to assess the modality under average and favorable tumor physiological conditions. RESULTS: By using ZCE025 under the baseline conditions, the model found that Fab was the most suitable form for cancer diagnosis, while 131l combined with F(ab')2 provided the highest tumor-to-bone marrow therapeutic ratio for cancer treatment. Sensitivity analysis showed that antibody permeability was the major barrier for antibody accretion in tumors. It also demonstrated that normal tissue antigen expression at a level lower than in the tumor had little effect on the therapeutic ratio. CONCLUSION: The model demonstrates that: (a) for radioimmunodetection, the most effective antibody form (Fab for ZCE025) was the lower mol weight form, yet not sensitive enough for hepatic metastasis detection; and (b) for radioimmunotherapy, a relatively fast-clearing antibody form (F(ab')2 for ZCE025) in combination with long half-life beta(-)-emitters was optimal, yet inadequate as the sole therapeutic modality for solid tumors.
Animals↗