Immunoscintigraphy of adenocarcinomas by means of radiolabeled F(ab')2 fragments of an anti-carcinoembryonic antigen monoclonal antibody: a multicenter study

F(ab')2 fragments of anti-carcinoembryonic antigen (CEA) monoclonal antibody F023C5, determined to be more suitable than intact IgG and Fab fragments for immunoscintigraphy, were labeled with 131I or conjugated to DTPA for instant 111In-labeling, and administered i.v. (2-3 mCi/0.5 mg) to 509 patients in 11 nuclear medicine departments: 284 patients had gastrointestinal adenocarcinomas, 204 had nongastrointestinal adenocarcinomas and 21 were control; serum CEA was elevated in 169 patients, normal in 115, and not determined in 225. The following results were obtained: (a) no adverse reactions; (b) tumor imaging in 324 patients (in particular, in 81.5% CEA-seropositive and in 69.0% CEA-seronegative patients); (c) no significant difference in sensitivity among the results of the 11 departments; (d) no significant difference in overall sensitivity between 131I-and 111In-labeled immunoradiopharmaceuticals; (e) the fraction of documented lesions imaged was 73.3% in CEA-seropositive and 53.7% in CEA-seronegative patients; (f) the detection of liver metastases was hampered, particularly when using the 111In-labeled reagent, by nonspecific radioactivity uptake; (g) the major cause of negative immunoscintigraphy results was a lack of CEA in tumor lesions, as documented by immunohistochemistry; (h) lesion size is also important since the sensitivity was 64% for lesions up to 2 cm in diameter and 84% for larger lesions; (i) many "unexpected" radiolocalizations were recorded. Most were identified as occult tumor lesions. In 35 patients, this finding contributed to the early detection of tumor recurrences.     

Current status of immunoscintigraphy in colorectal cancer--results of 5 years' clinical experiences

In 100 patients with suspected colorectal cancer, findings of conventional diagnostic methods were compared with immunoscintigraphy results. In a first trial 131-J-labelled F (ab') 2-fragments against CEA and CA 19-9 were used in 42 patients. Evidence was confirmed by surgical exploration in 69% of cases and by close follow-up examination in 31%. In a second trial 58 patients were included, and 81% of these were explored surgically. Conventional diagnostic methods achieved better results in both series in imaging liver and extrahepatic tumor manifestations, and in both series immunoscintigraphy was especially disappointing with regard to extrahepatic tumor diagnosis (sensitivity 23% and 38%, respectively). Accuracy could not be improved by technical modifications such as change of antibodies, radiolabels or imaging techniques. The value of immunoscintigraphy as a helpful tool for the operative management of metastatic or recurrent colorectal cancer must, therefore, be viewed critically.     

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 radio-immunotherapy of metastatic melanoma.     

Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery.

Patients with recurrent or metastatic medullary thyroid carcinoma (MTC) were referred for pretargeted immunoscintigraphy (Affinity Enhancement System; AES) and radioimmunoguided surgery (RIGS). Data collected from 13 patients establish that whole-body AES immunoscintigraphy revealed metastases < 360 mg and RIGS detected micrometastases (5-15 mg). All tissue samples removed by the surgeon were diagnosed by histology and immunohistochemistry of calcitonin to check the accuracy of IS and RIGS results. AES immunoscintigraphy is very sensitive. Of 34 metastases or recurrences detected, 22 had escaped physical examination or conventional imaging. The accuracy of RIGS was 86%, its sensitivity 75%, and its specificity was 90% (n = 208). IS and RIGS detected occult tumors that would have escaped surgery, clearly demonstrating clinical benefit. Serum calcitonin (normal, 10 pg/ml) and carcinoembryonic antigen (normal, 5 ng/ml) of two patients were restored to normal. In patients whose tumors were discovered, progression of their disease was slowed, as evidenced by the large decrease in serum calcitonin and carcinoembryonic antigen, an important prognostic factor. Surgery was canceled in one case where IS detected distant metastases out of surgical reach. Thus, AES immunoscintigraphy and RIGS might be of valuable help for the surgical management of medullary thyroid carcinoma.     

Radioimmunoimaging in malignant melanoma with 111In-labeled monoclonal antibody 96.5

A radiolabeled monoclonal antibody (96.5) reactive with an Mr 97,000 antigen found on over 80% of melanoma cell lines and tissue extracts was examined for its ability to detect malignant melanoma metastases in vivo. For imaging purposes, it was conjugated with diethyltriaminepentaacetic acid and subsequently labeled with 111In by chelation. Thirty-one patients with metastatic melanoma received single injections of monoclonal antibody 96.5 at concentrations ranging from 0.5 to 20 mg and at specific activities of 111In ranging from 0.125 to 4 mCi/mg. Total-body scans were performed at various time intervals following administration. No serious side effects were observed. Of a total of 100 previously documented metastatic sites, 50 imaged for a specificity of 50%. The number of sites imaged increased significantly as the amount of antibody administered increased relative to the average radiation dose. Considerable background uptake of isotope was observed in blood pool and other organs with gradual acquisition of label in tumor sites by 48 to 72 h. Hence, tumor imaging of melanoma using 111In-labeled monoclonal antibody 96.5 appeared feasible, especially at antibody doses above 2 mg.     

F-18 fluorodeoxyglucose positron emission tomography in the evaluation of distant metastases from renal cell carcinoma.

PURPOSE: We conducted a study to evaluate the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection of distant metastases from renal cell carcinoma (RCC).Materials and METHODS: Twenty-four patients with histologically proven clear-cell RCC undergoing surgical evaluation for possible resection of recurrent disease were investigated. All patients had suspected distant metastases based on conventional anatomic imaging techniques (computed tomography and magnetic resonance imaging). A total of 36 distant metastatic sites were identified. Pathology for all sites was obtained by biopsy or after surgical resection. RESULTS: Histologically documented distant metastases from RCC were present in 33 sites (21 patients). Overall sensitivity, specificity, and positive predictive value of FDG-PET for the detection of distant metastases from RCC was 63.6% (21 of 33), 100% (three of three), and 100% (21 of 21), respectively. The mean size of distant metastases in patients with true-positive FDG-PET was 2.2 cm (95% CI, 1.7 to 2.6 cm) compared with 1.0 cm in patients with false-negative FDG-PET (95% CI, 0.7 to 1.4 cm; P =.001). CONCLUSION: FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy.     

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.     

Pre-operative assessment of axillary lymph node status in patients with breast adenocarcinoma using intravenous 99mtechnetium mAb-170H.82 (Tru-Scint®AD™)

Immunoscintigraphy of the axilla has potential utility for the diagnosticand prognostic assessment of patients with breast adenocarcinoma.mAb-170H.82 is a murine monoclonal antibody (mAb) derived against syntheticThomsen-Friedenreich (TF) antigen. Tru-Scint®AD, a^99mTc-mAb-170H.82 immunoconjugate, has previously been shownto localize in various human adenocarcinomas. The purpose of this study wasto evaluate the accuracy of this immunoconjugate in the pre-operativeassessment of axillary lymph nodes in patients with known breastadenocarcinoma. Sixteen patients with documented primary breast cancer wereinjected intravenously with 1 mg of immunoconjugate (radioactivity 1.8 GBq)and imaged 22–24 hrs post-injection. Both planar and single photonemission computed tomographic (SPECT) images were obtained and reviewed in ablinded fashion. Imaging results were compared with surgical andpathological findings. Seven of 16 patients were found to havehistologically positive axillary nodes: 5 of these sites were detected byimmunoscintigraphy (sensitivity = 71%). Nine patients hadpathologically disease-free axillary nodes: only 1 of these wasmisidentified as positive by immunoscintigraphy(specificity = 89%). These results suggest thatimmunoscintigraphy with ^99mTc-mAb-170H.82 has promise in thedetection of axillary lymph node involvement in patients with breast cancer.Further studies are warranted to define the role of immunoscintigraphy inaxillary staging.     

Immunoscintigraphy with positron emission tomography: gallium-68 chelate imaging of breast cancer pretargeted with bispecific anti-MUC1/anti-Ga chelate antibodies

Pretargeting techniques that are based on the sequential administrations of bispecific antitumor/antimetal chelate antibodies (BS-MAbs), a blocker to saturate the anti-chelate binding sites of the BS-MAb still present in the circulation, and the radiolabeled chelate are suitable to increase tumor-to-normal tissue contrasts and enable positron emission tomography (PET) as an imaging method. As demonstrated in the nude mouse model, a combination of pretargeted immunoscintigraphy and PET markedly improved the detection of tumor xenografts. With the presented preliminary clinical trial, we attempted to assess the efficacy of pretargeting and PET for breast cancer localization in patients. The BS-MAb used for pretargeting was synthesized from the F(ab')(2) fragments of the anti-MUC1 MAb 12H12, which reacts with the vast majority of breast tumors, and the F(ab') fragments of an anti-gallium (Ga) chelate MAb via a mixed functional chemical linker. For labeling of the Ga-chelate, we used the short-lived positron emitter Ga-68 (t(1/2), 68 min; beta(+), 88%). The dose and time schedule of pretargeting was deduced from previous animal experiments. Ten patients with biopsy-proven, primary breast carcinoma were infused with 10 mg of the BS-MAB: Eighteen h later, they received i.v. injections of 10.7 mg of a blocker and, 15 min later, 9.6 microg of the Ga chelate labeled with 230-300 MBq of (68)GA: PET imaging was started 60-90 min after injection of the (68)Ga chelate. Average tumor-to-blood and tumor:normal breast tissue ratios were 0.9 and 3.0 at 1 h postinjection. Tumor uptake amounted to approximately 0.003% iD/g corresponding to a standard uptake value of approximately 2. Blood clearance of the (68)Ga chelate showed a t(1/2) beta of approximately 100 min. Fourteen of 17 known lesions, averaging 25 +/- 16 mm in size, were clearly visualized as foci of increased activity with PET. No false-positive but three false-negative readings were obtained. An enhanced, bilateral activity uptake in the whole breast parenchyma, found in 4 of the 10 patients, compromised the recognition of these tumor sites. Although the shedding of the MUC1 antigen and the comparatively low tumor affinity of the BS-MAb, common to all anti-mucin MAbs, proved not to be optimal for increasing tumor:tissue ratios with a pretargeting technique, PET imaging offered better sensitivity for the detection of breast cancer at low tumor contrasts than conventional immunoscintigraphy. This could be demonstrated by the clear visualization of tumor sites 10 mm in size, which contrasted only by a factor of 2 from surrounding normal breast tissue.     

Scintigraphic detection of metastatic melanoma using indium 111/DTPA conjugated anti-gp240 antibody (ZME-018)

We evaluated the toxicity, pharmacokinetics, and localization of a monoclonal IgG2 alpha murine anti-human melanoma (gp240) antibody (ZME-018) that recognizes a tumor-associated cell surface glycoprotein of 240,000 molecular weight present in most melanomas. The antibody was conjugated with DTPA (diethylenetriamine pentaacetic acid) and labeled by chelation of 111In. One mg of antibody labeled with 5 mCi of 111In was infused, together with 0 to 40 mg of "cold" carrier ZME-018. The blood clearance, urinary excretion, and in vivo localization were determined in 26 patients. Scintigraphic images were obtained at 24 hours and 72 hours in all patients. Mild toxicity occurred in one patient. The half-time clearance of labeled monoclonal murine antibody (MoAb) from the blood increased from 16.1 hours at an antibody dose of 1 mg to 35.9 hours at 40 mg. Males showed faster clearance from the blood than did females or a single castrated male, perhaps due to selective concentration of antibody in the testes. Nonspecific uptake in liver, spleen, bone marrow, and intestine was seen in all patients. The percentage of known metastatic foci detected increased with the total dosage of antibody, from 23% at doses less than or equal to 5 mg, to 65%, 87% and 78% for 10, 20, and 40 mg, respectively. We conclude that at doses of greater than or equal to 10 mg, ZME-018 is a safe and potentially useful agent for the scintigraphic detection of metastatic malignant melanoma.     

Quantitative analysis of antibody localization in human metastatic colon cancer: a phase I study of monoclonal antibody A33

A33 is a mouse immunoglobulin G2a (IgG2a) monoclonal antibody (mAb) that detects a heat-stable, protease- and neuraminidase-resistant epitope. The antigen is homogeneously expressed by virtually all colon cancers and in the colon mucosa but not other epithelial tissues. The biodistribution and imaging characteristics of iodine-131 (131I)-mAbA33 were studied in colorectal carcinoma patients with hepatic metastases. Antibody labeled with 2 to 5 mCi of 131I was administered intravenously (IV) 7 to 8 days before surgery at five dose levels, ranging from 0.2 mg to 50 mg, with three or more patients entered at each dose level. In addition, three patients received 2 mg 131I-mAbTA99 (an isotype-matched control mAb) together with 125I-mAbA33. Evaluation included whole-body imaging with a gamma camera, technetium-99 (99mTc)-human serum albumin blood pool scans, liver/spleen scans, abdominal computed tomographic (CT) scans, hepatic arteriograms, antibody pharmacokinetics, and assessment of antibody distribution in biopsied malignant and normal tissues. Selective mAbA33 localization to tumor tissue was demonstrated in 19 of 20 patients, and external imaging correlated with surgical inspection, pathologic examination, and tissue radioactivity. One week after antibody administration, tumor:liver ratios ranged from 6.9:1 to 100:1 and tumor:serum ratios from 4.1:1 to 25.2:1. 99mTc-albumin blood pool studies showed that liver metastases were hypovascular, emphasizing the selective localization of mAbA33 despite poor tumor-blood flow. Control mAbTA99 studies showed mAbA33 localization was antigen-specific; tumor:liver ratios were 2.3- to 45-fold higher for specific antibody. In metastatic lesions, radioisotope was localized primarily in the viable periphery; however, even the necrotic tumor core concentrated specific antibody. External imaging showed isotope visualization in some patients' large bowel; whether this represents specific antibody uptake or gastric iodine secretion is unclear.     

Value of peptide receptor scintigraphy using (123)I-vasoactive intestinal peptide and (111)In-DTPA-D-Phe1-octreotide in 194 carcinoid patients: Vienna University Experience, 1993 to 1998.

PURPOSE: To report our experience with both (123)I-vasoactive intestinal peptide (VIP) and (111)In-DTPA-D-Phe(1)-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients. PATIENTS AND METHODS: One hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with (111)In-DTPA-D-Phe(1)-OCT for imaging purposes, while 133 patients underwent scanning with both (123)I-VIP and (111)In-DTPA-D-Phe(1)-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging. RESULTS: Primary or recurrent carcinoid tumors could be visualized with (111)In-DTPA-D-Phe(1)-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, (111)In-DTPA-D-Phe(1)-OCT was found to be superior to (123)I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with (111)In-DTPA-D-Phe(1)-OCT and (123)I-VIP, respectively. CONCLUSION: Both peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with (111)In-DTPA-D-Phe(1)-OCT scintigraphy being more sensitive than (123)I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.     

Gamma probe location of 111indium-labeled B72.3: an extension of immunoscintigraphy.

Eight colorectal and 5 ovarian cancer patients were evaluated with preoperative immunoscintigraphy and intraoperative gamma probe detection of 111indium-labeled monoclonal antibody B72.3. Immunoscintigraphy detected the presence of tumor in every patient shown to have tumor at surgery. There was one false-positive scan. A total of 21 pathologically verified lesions were identified at surgery in the 11 patients with tumor. Immunoscintigraphy localized 12 (57%) and intraoperative gamma probe detection located 17 (81%) of the lesions. Intraoperative probe detection located 6 of 8 lesions smaller than 1 cm and 3 lesions that were not identified on initial surgical exploration. The gamma probe offers information that is complementary to immunoscintigraphy in that (1) it aids the surgeon in locating intra- and extra-abdominal lesions previously identified by immunoscintigraphy, (2) it locates lesions too small to be seen by immunoscintigraphy alone, (3) it locates lesions that otherwise might be missed at surgery, and (4) it provides objective evidence for adequacy of surgical resection of cancer in the abdominal cavity.     

Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer.

PURPOSE: ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling. We demonstrated previously the possibility to target and selectively deliver therapeutic substances to tumor vasculature in experimental animal models using a human recombinant antibody fragment, L19, specific for the ED-B domain of fibronectin. Here we evaluate the possibility of targeting primary tumors and metastatic lesions in cancer patients through immunoscintigraphy using (123)I-labeled dimeric L19 [L19(scFv)(2)]. EXPERIMENTAL DESIGN: Twenty patients (34-79 years of age) with lung, colorectal, or brain cancer, whose tumors had been confirmed by imaging techniques and/or histologically, were admitted to the immunoscintigraphic investigation. RESULTS: The dimeric L19 antibody selectively localized in tumor lesions in aggressive types of lung cancer and colorectal cancer. Because ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling, L19(scFv)(2) is able to distinguish between quiescent and actively growing lesions. No side effects were observed. CONCLUSIONS: The ability of L19(scFv)(2) to target tumors in patients provides the foundations for new therapeutic applications, in which the L19 antibody is engineered to selectively deliver bioactive molecules to primary tumors as well as to metastases.     

Three-step monoclonal antibody tumor targeting in carcinoembryonic antigen-positive patients

We describe a method to postlabel, in vivo, biotinylated monoclonal antibodies pretargeted onto tumor deposits when most of the non-tumor-bound antibodies have already been cleared as avidin-bound complexes. The application of this principle to tumor detection by immunoscintigraphy was tested in 20 patients with histologically documented cancer and increased circulating carcinoembryonic antigen levels. One mg of biotinylated anti-carcinoembryonic antigen monoclonal antibody (FO23C5) was administered i.v. (first step). After 3 days, 4-6 mg of cold avidin were injected i.v. (second step), followed 48 h later by 0.2-0.3 mg of a biotin derivative labeled with 111In (2-3 mCi) (third step). No evidence of toxicity was observed. Whole body radioactivity distribution was measured in five patients at various intervals postinjection by the conjugate counting technique. Tumors and metastases were detected in 18 of 19 patients (the remaining patient was a true negative) within 3 h after administration of 111In-biotin by planar or single photon emission tomography imaging. At the time of imaging, tumor/blood pool ratio was 5.5 +/- 3.2, and tumor/liver ratio was 6.7 +/- 3.9. Blood clearance of 111In-biotin was multiexponential, with the fast component having a t1/2 of 5 +/- 3 min. Urinary excretion of radioactivity over 3 h was 63.5 +/- 4.9% of the injected dose. Radioactivity at 3 h was 6.5 +/- 1.8% in blood, 1.6 +/- 0.3% in the kidney, and 2.4 +/- 0.6% in the liver. This approach represents an improvement in immunoscintigraphic techniques for tumor localization. The potential use for radioimmunotherapy is discussed.     

Immunoscintigraphy and pharmacokinetics of indium-111-labeled ZME-018 monoclonal antibody in patients with malignant melanoma

Immunoscintigraphic and pharmacokinetic characteristics of 111In-labeled ZME-018 monoclonal antibody were examined in 8 patients with malignant melanoma. Each patient received a single intravenous infusion of 20 mg of ZME-018, coupled to 3 mCi of 111In without any acute toxicity. Scintigrams were taken 1, 3, and 6 days after the administration, and blood and urine samples were also taken frequently. Rapid clearance of some radioactivity was seen in early urine samples in the form of 111In DTPA, but after 1 day, urinary excretion of radioactivity was slow and steady, with an average of 2.5% of the injected dose excreted per day. The scans demonstrated that there was blood retention of radioactivity in the heart and great vessels 1 day after infusion and considerable clearance from the blood pool occurred by 3 days. However, 111In was deposited in the liver, spleen and bone for up to 6 days. The optimal time for imaging appeared to be at 3 days. Nineteen out of 26 known lesions or 6 out of 8 patients were positive. There were 21 lesions detected that were not suspected during the work-up the patient. Five patients developed human anti-mouse antibody in the serum by 3 weeks. These results suggest that immunoscintigraphy with 111In-labeled ZME-018 antibody is safe and useful for the detection of metastatic lesions in a selected group of patients with malignant melanoma.     

Clinical studies on the radioimmunodetection of tumors containing alpha-fetoprotein

This study reports the use of radiolabeled antibodies to alpha-fetoprotein for the detection and localization of hepatocellular and germ cell carcinomas. Twelve patients with histories of histologically-confirmed neoplasia received a total dose between 1.0 and 4.4 mCi of 131I-labeled goat IgG prepared against human alpha-fetoprotein. Total-body photoscans were taken with a gamma scintillation camera at various intervals after injection of the radioactive antibody. Computer subtraction of radioactive technetium background images from the antibody 131I scans permitted the visualization of all tumor sites known to be present in 4 patients with either primary hepatocellular cancer or metastatic germ cell carcinoma of the testis. In contrast to the results with the specific antibody, radioactive normal goat IgG given to one of these patients with metastatic embryonal carcinoma of the testis failed to show equivalent localization. Among 8 patients with diverse neoplasms not believed to contain alpha-fetoprotein, 5 of 19 tumor sites showed radioactive antibody accretion, although significantly less than in the patients with liver or testicular cancer. Circulating antigen levels of up to 15,000 ng per milliliter did not prevent successful tumor imaging after intravenous injection of the radioantibody. This investigation indicates that alpha-fetoprotein-containing tumors can be detected and localized in vivo by the method of radioimmunodetection.     

Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma

Lymphoid cells infiltrating into human tumors can be expanded in vitro in medium containing interleukin-2 (IL-2). Adoptive transfer of these tumor-infiltrating lymphocytes (TIL) mediates potent antitumor effects in murine tumor models. Clinical trials to evaluate the efficacy of these cells in patients with advanced cancer are underway. We have investigated whether infused TIL labeled with indium 111 (111In) oxine can traffic and localize to metastatic deposits of tumor. Six patients with metastatic malignant melanoma who had multiple sites of subcutaneous, nodal, and/or visceral disease were the subjects of the study. The patients received cyclophosphamide 36 hours before receiving the intravenous (IV) infusion of TIL followed by IL-2 IV every eight hours. The distribution and localization of the TIL were evaluated using serial whole body gamma camera imaging, serial blood and urine samplings, and serial biopsies of tumor and normal tissue. 111In-labeled TIL localized to lung, liver, and spleen within two hours after the infusion of activity. Activity in the lung diminished within 24 hours. As early as 24 hours after injection of 111In-labeled TIL, localization of TIL to sites of metastatic deposits was demonstrated in all six patients using either imaging studies or biopsy specimens or both. 111In activity in tumor tissue biopsies ranged from three to 40 times greater than activity in normal tissue. A progressive increase in the radioactive counts at sites of tumor deposit was seen. This study shows that labeled TIL can localize preferentially to tumor, and provides information concerning the possible mechanism of the therapeutic effects of TIL.     

Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma

Monoclonal antibody (MAb) B72.3 has been shown to have selective reactivity for a wide range of carcinomas (colorectal, ovarian, breast, lung, gastric, and endometrial) versus normal adult tissues. 131I-Labeled B72.3 IgG has recently been shown to selectively bind carcinoma lesions when administered i.v. in patients with metastatic colorectal cancer. We report here the first direct comparison of i.p. administered [131I]B72.3 IgG to specifically localize metastatic carcinoma. Three of 10 patients studied were negative for tumor detection by both CAT scan and X-ray but were positive for tumor localization via gamma scanning i.p. administered 131I-labeled MAb B72.3 IgG. Direct analyses of biopsy specimens of carcinoma and normal tissues demonstrated ratios of greater than 70:1 (based on percentage of injected dose/mg) for tumor MAb localization versus normal tissues. Specificity of [131I]B72.3 tumor targeting was demonstrated by the concomitant administration of an equal dose of an 125I-labeled isotype identical (IgG1) control MAb. Simultaneous i.p. administration of [131I]B72.3, and i.v. administration of [125I]B72.3 in individual patients demonstrated: peritoneal implants are targeted more efficiently via i.p. MAb administration, and hematogenously spread and lymph node metastases as well as local recurrences are targeted more efficiently by i.v. administered MAb. No antibody toxicity was observed in any patients. Pharmacokinetics of MAb clearance demonstrated that only 10 to 30% of the i.p. administered MAb was found in plasma. These studies thus demonstrate the efficacy of intracavitary MAb administration as well as the advantage of the concomitant use of intracavitary and i.v. administered MAbs for tumor targeting and for potential MAb guided therapy of metastatic carcinoma.     

Role of technetium 99m-labeled monoclonal antibody in the management of melanoma patients.

PURPOSE: A study was performed to assess the usefulness of a radiolabeled monoclonal antibody (MoAb; technetium 99m NR-ML-05 Fab) as a detecting agent, as well as to evaluate its role in the overall decision-making process in the management of cutaneous malignant melanoma. PATIENTS AND METHODS: Twelve patients with histologically confirmed primary cutaneous melanoma and palpable regional nodes were injected with MoAb NR-ML-05 Fab, radiolabeled with 20 to 30 mCi of 99mTc. Whole-body anterior and posterior images were obtained. Left and right lateral views of the head and anterior and posterior views of the chest, abdomen, pelvis, and extremities were obtained, as were selected single-photon emission computed tomographic (SPECT) views of regional lymph nodes and areas of known or suspected lesions. RESULTS: In nine of 12 patients, clinical and/or MoAb evolution identified 30 discrete sites of suspected melanoma. The remaining three patients showed no positive sites, and there was no evidence of metastatic melanoma. All 30 sites were examined microscopically, and melanoma was confirmed histologically in 23. The remaining seven were negative. MoAb imaging detected 21 (true-positive) but failed to detect two (false-negative) lesions. Sensitivity was 91% (21 of 23); positive predictive value was 95% (21 to 22). CONCLUSIONS: MoAb imaging seems to provide an excellent way to obtain information with regard to the metastatic status of melanoma patients. Immunocytochemistry showed that MoAb (NR-ML-05) is as sensitive as the S-100 antibody and probably more sensitive than the commercially available antimelanoma antibody HMB-45.