Accurate quantification of 131I distribution by gamma camera imaging.

The development of targeted therapy requires that the concentration of the therapeutic agent can be estimated in target and normal tissues. Single photon emission tomography (SPET), with and without scatter correction, and planar imaging using 131I have been compared to develop a method for investigation of targeted therapy. Compton scatter was investigated using line spread functions in air and water, these data were used to set a second peak, adjacent to the photopeak, for scatter correction. The system was calibrated with an eliptical phantom containing sources in background activity of various intensities. Scatter corrected reconstructions gave accurate estimates of activity in the sources regardless of background activity. For planar scanning and SPET without scatter correction there was an overestimate of activity in the source of 290% and 40% respectively. The validity of this method was confirmed in patients by comparing activity in the cardiac ventricles measured by SPET with scatter correction with that in a simultaneous blood sample. A coefficient of correlation of 0.955 was achieved with 25 data points. SPET with scatter correction was compared with planar imaging in measuring activity in the liver and spleen of patients receiving 75 mCi 131I-antibody to CEA intravenously. Planar imaging gave significantly higher values than SPET for the spleen (t = 5.4, P less than 0.001 by the paired t-test) but no significant difference for the liver. SPET with scatter correction forms a basis for an improved technique of quantifying the targeting efficiency.

Second antibody for improvement of antibody imaging: liposome-entrapped and free preparations in animal and human studies.

When anti-tumour antibodies are given systematically for tumour imaging or therapy, second antibody directed against the first (anti-tumour) antibody can be used to accelerate clearance of first antibody, thus improving discrimination between tumour and normal tissues. Liposome-entrapped, and free second antibodies (LESA and FSA, respectively) have been compared in an animal tumour model system and in patients with cancer. Nude mice bearing xenografts of human colon carcinoma were given goat antibody to carcino-embryonic antigen (CEA) as first antibody and horse anti-goat second antibody. Patients with gastrointestinal carcinomas received i.v. 131I-labelled goat anti-CEA or mouse monoclonal 17-1A first antibody and unlabelled horse angi-goat or rabbit anti-mouse second antibody, respectively. Antibody distribution was studied by serial gamma camera imaging. The effectiveness of LESA and FSA depended on dose. Tumour-to-blood ratios were increased up to eight-fold by either method in animals. Tumour imaging was enhanced among 15 patients with gastrointestinal cancer and tumour was correctly identified at five sites where it was not seen by a background subtraction method. No significant toxicity occurred in patients nor in rabbits studied for evidence of immune complex mediated disease. LESA and FSA appear to be equally effective.

Antibody distribution and dosimetry in patients receiving radiolabelled antibody therapy for colorectal cancer.

The distribution of iodine-131 (131I) labelled antibody to carcinoembryonic antigen (CEA) has been studied in 16 patients with colorectal cancer. Levels of tumour and normal tissue radioactivity were measured by serial gamma-camera imaging and counting of blood and urine. Maximum concentrations were found in tumour 8 h after administration and varied up to 9-fold in different patients. Higher levels were found on average in tumour than in any other tissue. Liver, lung and blood were the other tissues in which antibody was concentrated relative to the rest of the body. Antibody cleared from all these tissues over 1 week. Second antibody directed against the antitumour (first) antibody was given 24 h after first antibody in order to accelerate clearance from the blood. This increased the tumour to blood ratio but had little effect on other tissues. Cumulative radiation dose to tumour and normal tissue was estimated. In patients with the most efficient localisation the tumour to body ratio was 20:1 and tumour to blood ratio 5:1. This may be sufficient for effective therapy of cancer in patients selected for efficient antibody localisation. The data may be used to estimate the effect of different therapeutic strategies. For instance, in the time after second antibody administration the average tumour to blood ratio of radiation dose was 11:1, suggesting that two phase systems in which the therapeutic modality is given after a good tumour to normal tissue ratio is obtained may be effective for the majority of patients.

Repeated antitumour antibody therapy in man with suppression of the host response by cyclosporin A.

Antibody targeted therapy of cancer results in anti-antibody production which prevents repeated treatment. Cyclosporin A (CsA) has been used to suppress this response in patients treated with a radiolabelled antibody to carcinoembryonic antigen (CEA). Patients with CEA producing tumours received a minimum of two courses consisting of an injection of radiolabelled antibody and CsA, 24 mg kg-1 day-1, for 6 days; each course was given at 2 week intervals. Two weeks after the completion of the second course the mean human antimouse antibody (HAMA) levels were 3.5 micrograms ml-1 (s.d. 2.7) in 3 patients receiving CsA and 1,998 micrograms ml-1 (s.d. 387) in 3 patients not receiving the drug. Clearance of antitumour antibody was accelerated and tumour localisation absent when HAMA levels exceeded 30 micrograms ml-1. With lower levels of HAMA in the CsA-treated patients, further antitumour antibody accumulated in the tumour after each dose. Further therapy with antitumour antibody and CsA lead to the development of HAMA, but this was less than 25% of the amount in patients not given CsA. In this preliminary study up to 4 times as many doses of antitumour antibody could be usefully given when CsA was used. This increases the potential for effective antibody targeted therapy of cancer.

Quantitation in 131I-radioimmunotherapy using SPECT.

Quantitation from planar imaging and single photon emission computed tomography (SPECT) were compared in phantom studies and in patients receiving therapeutic doses of 131I-labelled anti-CEA. During the reconstruction of the data for SPECT quantitation attenuation correction and a correction for Compton scatter were used. The limitations of both methods were examined using the phantom studies and it was shown that practical SPECT quantitation could be achieved in patients given therapeutic doses of 131I-labelled anti-CEA, and furthermore, that SPECT appeared to give a more accurate estimate of the activity concentration.