Ja Ledermann

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.

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.

Cyclosporin A prevents the anti-murine antibody response to a monoclonal anti-tumour antibody in rabbits

Repeated therapy of cancer with mouse monoclonal antibodies frequently produces antibodies directed against the administered antibody. We have investigated the ability of cyclosporin A (CsA) and the use of ultracentrifuged antibody to prevent the formation of anti-antibodies in rabbits. Courses of CsA, 20 mgkg-1 day-1, were given intramuscularly for 6 days to rabbits and a mouse monoclonal anti-human chorionic gonadotrophin antibody was given intravenously on day 2 with or without ultracentrifugation to remove microaggregates. The whole course was repeated after an interval of two weeks. Rabbit anti-mouse antibody production was prevented in all 8 animals that were given CsA and ultracentrifuged preparation (non UC-W14). Anti-mouse antibody was produced by all the animals that were not given CsA. A further dose of mouse antibody eight weeks after CsA demonstrated that immunological recovery had occurred in all four animals re-challenged with non UC-W14 but only 3/7 animals given an UC-W14 preparation. This suggests that CsA and ultracentrifugation facilitate the induction of immunological tolerance. The complete suppression of antibody production which could be achieved justifies a clinical trial of CsA and ultracentrifugation of antibody.

Weekly etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide plus vincristine (EMA/CO): a phase II study in advanced gastric carcinoma.

A total of 27 patients with measurable/evaluable metastatic or locally advanced gastric carcinoma were given combination chemotherapy comprising etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO). Ten achieved partial remission, giving a response rate of 37% (95% CI; 21.7%-66.3%), 12 attained stable disease, whereas five had disease progression despite treatment. Drug toxicity was moderate to severe. Five of those who achieved partial remission underwent an attempt to resect residual disease which was successful in only three patients.