A phase I radioimmunotherapy trial evaluating 90yttrium-labeled anti-carcinoembryonic antigen (CEA) chimeric T84.66 in patients with metastatic CEA-producing malignancies.

Chimeric T84.66 (cT84.66) is a genetically engineered human/murine chimeric IgG, with high affinity and specificity to carcinoembryonic antigen (CEA). The purpose of this Phase I dose escalation therapy trial was to evaluate the toxicities, biodistribution, pharmacokinetics, tumor targeting, immunogenicity, and organ and tumor absorbed dose estimates of cT84.66 labeled with 90Y. Patients with metastatic CEA-producing malignancies were first administered 5 mCi 111In-labeled DTPA-cT84.66 (5 mg), followed by administration of the therapy dose of 90Y-labeled DTPA-cT84.66 1 week later. The therapy infusion was immediately followed by a 72-h administration of DTPA at 250 mg/m2/24 h. Dose levels of administered activity ranged from 5 to 22 mCi/m2 with three to six patients per level. Serial nuclear scans, blood samples, and 24-h urine collections were performed out to 5 days after infusion. Human antichimeric antibody response was assayed out to 6 months. Patients were administered up to 3 cycles of therapy every 6 weeks. Radiation absorbed doses to organs were estimated using a five compartment model and MIRDOSE3. Twenty-two patients received at least one cycle of therapy, with one individual receiving two cycles and two receiving three cycles of therapy. All were heavily pretreated and had progressive disease prior to entry in this trial. Reversible leukopenia and thrombocytopenia were the primary dose-limiting toxicities observed. Maximum tolerated dose was reached at 22 mCi/ m2. In general, patients with liver metastases demonstrated more rapid blood clearance of the antibody. Thirteen patients developed an immune response to the antibody. Average radiation doses to marrow, liver, and whole body were 2.6, 29, and 1.9 cGy/mCi 90Y, respectively. Dose estimates to tumor ranged from 66 to 1670 cGy (8.7 to 52.2 cGy/mCi 90Y) for each cycle of therapy delivered. Although no major responses were observed, three patients demonstrated stable disease of 12-28 weeks duration and two demonstrated a mixed response. In addition, a 41-100% reduction in tumor size was observed with five tumor lesions. 90Y-labeled cT84.66 was well tolerated, with reversible thrombocytopenia and leukopenia being dose limiting. Patients with extensive hepatic involvement by tumor demonstrated unfavorable biodistribution for therapy with rapid blood clearance and poor tumor targeting. Average tumor doses when compared with red marrow doses indicated a favorable therapeutic ratio. Stable disease and mixed responses were observed in this heavily pretreated population with progressive disease. This trial represents an important step toward further improving the therapeutic potential of this agent through refinements in the characteristics of the antibody and the treatment strategies used. Future trials will focus on the use of peripheral stem cell support to allow for higher administered activities and the use of combined modality strategies with radiation-enhancing chemotherapy drugs. Further efforts to reduce immunogenicity through humanization of the antibody are also planned. Finally, novel engineered, lower molecular weight, faster clearing constructs derived from cT84.66 continue to be evaluated in preclinical models as potential agents for radioimmunotherapy.

Truncation of blood curves to enhance imaging and therapy with monoclonal antibodies.

Targeting of monoclonal antibody (Mab) to solid tumor sites is a function of the blood curve of activity versus time. It has been suggested that the blood curve be artificially reduced to approach zero so that the contrast between tumor and blood uptake is maximized. We analyzed tumor uptake as a function of the time tc of blood curve truncation. By using a convolution approach, we were able to find the optimal times for setting the blood curve to zero in either diagnostic or therapeutic animal examples. Two iodinated cT84.66 anti-CEA engineered fragments, diabody and minibody, were considered using previous data from nude mouse studies involving the LS174T colorectal tumor model. Figures of merit (FOMs) were used to compare ordinary and truncated blood curves and their associated tumor accumulations. Using a 1231 label, it was seen that the appropriate time for diagnostic truncation occurred when tumor uptake, as measured, was a maximum. The corresponding point for therapy (with 1311 as a label) was at infinite time. We also demonstrated that the use of traditional indices led to ambiguities in the choice of truncation times. The traditional therapy index, the ratio of the integral of the tumor uptake to the integral of the blood uptake, was found to be a numerical constant independent of tc. This ratio was proved to be the integral of the tumor impulse response function. Use of such convolution techniques to assess truncation of the perfused material is probably also applicable to multistep processes as well as to lesion targeting with other tumor-specific pharmaceuticals.

A radionuclide therapy treatment planning and dose estimation system.

UNLABELLED: An object-oriented software system is described for estimating internal emitter absorbed doses using a set of computer modules operating within a personal computer environment. The system is called the Radionuclide Treatment Planning and Absorbed Dose Estimation System (RTDS). It is intended for radioimmunotherapy applications, although other forms of internal emitter therapy may also be considered. METHODS: Four software modules interact through a database backend. Clinical, demographic and image data are directly entered into the database. Modules include those devoted to clinical imaging (nuclear, CT and MR), activity determination, organ compartmental modeling and absorbed dose estimation. RESULTS: Both standard phantom (Medical Internal Radiation Dose [MIRD]) and patient-specific absorbed doses are estimated. All modules interact with the database backend so that changes in one process do not influence other operations. Results of the modular operations are written to the database as computations are completed. Dose-volume histograms are an intrinsic part of the output for patient-specific absorbed dose estimates. A sample dose estimate for a potential 90Y monoclonal antibody is described. CONCLUSION: A four-module software system has been implemented to estimate MIRD phantom and patient-specific absorbed doses. Computations of the doses and their statistical distribution for a pure beta emitter such as 90Y take approximately 1 min on a 300 MHz personal computer.

Initial experience evaluating 90yttrium-radiolabeled anti-carcinoembryonic antigen chimeric T84.66 in a phase I radioimmunotherapy trial.

Chimeric T84.66 (cT84.66) is a high-affinity (5 x 10(10) M-1) anti-carcino-embryonic antigen (CEA) IgG1. In a recently completed pretherapy imaging trial, 111In-labeled cT84.66 demonstrated targeting of CEA-producing metastatic sites and low immunogenicity, with human antichimeric antibody (HACA) response in only 1 of 15 patients after a single administration. The purpose of the present study was to evaluate cT84.66-diethylenetriaminepentaacetic acid labeled with 90Y in a dose-escalation Phase I trial. Patients with metastatic CEA-producing malignancies received imaging doses of 5 mCi 111In-labeled cT84.66 first, followed 1-2 weeks later by 5 mg cT84.66 labeled with the therapeutic dose of 90Y. Immediately following the therapeutic infusion, diethylenetriaminepentaacetic acid was administered by continuous i.v. infusion over 3 days at 250 mg/m2 body surface area/24 h. Biodistribution, tumor targeting, absorbed radiation dose estimates, antibody clearance, and HACA response were evaluated through blood samples, 24-h urine collections, and nuclear images performed at serial time points after infusion. To date, three patients with metastatic colorectal cancer have been evaluated at the first dose level of 5 mCi/m2. No side effects were associated with antibody administration. Localization of the antibody to nonhepatic metastatic sites was observed. Size-exclusion high-performance liquid chromatography demonstrated the formation of CEA:antibody complexes in serum in all three patients. A significant variation among patients in the clearance rate of the antibody and complexes from blood to liver was seen, which resulted in a reciprocal relationship between estimated liver dose and red marrow dose. Patients who demonstrated faster clearance to liver demonstrated greater excretion of a low-molecular-weight metabolite through the urine. Two patients developed HACA response, which persisted at 4 months after therapy. At this first dose level, no tumor responses were seen and reversible grade 1 thrombocytopenia was observed in 2 patients. cT84.66 demonstrated effective localization in CEA-producing tumors. Its low immunogenicity after a single administration makes it attractive for further evaluation as a radioimmunotherapeutic agent. However, further evaluation is needed to determine whether its immunogenicity will remain low after multiple administrations. Additionally, in two of the three patients, we identified rapid clearance of the antibody to the liver. This underscores the need to identify, characterize, and understand further those factors that influence the biodistribution and clearance of anti-CEA antibodies to allow for better selection of patients for therapy and rational planning of radioimmunotherapy.

Comparison of immunoscintigraphy and computerized tomography in identifying colorectal cancer: individual lesion analysis.

Monoclonal antibody scintigraphy with 111In-ZCE025 was used in presurgical staging of 45 patients prior to abdominal exploration for primary, recurrent or metastatic colorectal carcinoma. A total of 186 lesions were identified, of which 147 were evaluated by abdominal surgery and pathology. Sensitivity was 40.5% (49 of 121) for immunoscintigraphy (IS), 61.2% (74 of 121) for computerized tomography (CT), and 72.7% (88 of 121) for IS and CT combined. The positive predictive value was 83.1% (49 of 59) for IS and 88.1% (74 of 84) for CT. Sensitivity of IS was 100% (23 of 23) for primary tumors, 17.7% (11 of 62) for hepatic metastases, and 41.7% (15 of 36) for extrahepatic abdominal metastases. Of the 50 hepatic lesions evaluated by single-proton emission computerized tomography, 11 were localized by IS. Only one was visualized by planar scintigraphy. Sensitivity of CT was 87% (20 of 23) for primary tumors, 67.7% (42 of 62) for hepatic metastases, and 33.3% (12 of 36) for extrahepatic abdominal metastases. Sensitivity of IS combined with CT was 72.6% (45 of 62) for hepatic and 55.6% (20 of 36) for extrahepatic abdominal metastases. Of 24 malignant lesions measured by the pathologist to be less than 3.0 cm (maximum dimension), 7 (29.2%) were detected by IS and 3 (12.5%) by CT. Of 28 malignant lesions greater than 3.0 cm, 23 (82.1%) were detected by IS and 24 (85.7%) by CT. Overall, IS and CT complemented each other in presurgical staging of colorectal carcinoma. IS was of greater value for identification of extrahepatic and small metastases. CT was more effective for identification of hepatic metastases.

Computed tomography in endobronchial neoplasms.

Computed tomography (CT) was performed in 86 patients with bronchoscopically proven endobronchial neoplasms. There were 76 primary and 10 metastatic lesions. CT correctly identified the abnormal airway in 95% of cases (82/86) by demonstrating either nodule, mass, or stricture. A discrete endobronchial nodule was seen in 55% (47/86). There was good morphological correlation of CT with bronchoscopic findings (89% for discrete nodule, 80% overall). Appropriate atelectasis was noted in 80% (69/86) of cases. CT is sensitive in detecting and localizing endobronchial neoplasms and correlates well with bronchoscopic findings.