A phase‐i study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin a to suppress the immune response

Abstract

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

Orthotopic xenografts of human melanoma and colonic and ovarian carcinoma in sheep to evaluate radioimmunotherapy

“…This study describes the development of a robust and practical large animal model of human tumours xenografted in cyclosporinimmunosuppressed sheep. Preliminary results indicate that tumour uptake of anti-CEA monoclonal antibodies in human colon cancer xenografts in these sheep is comparable with that reported in clinical trials using the same radiolabelled antibody in patients with colon carcinoma (Ledermann et al, 1991). These patients were also treated with cyclosporin, to suppress HAMA response.…”

Treatment with Unlabeled mAb BR96 After Radioimmunotherapy with 177Lu-DOTA-BR96 in a Syngeneic Rat Colon Carcinoma Model

“…25 Cyclosporin A has previously been used to prevent the formation of anti-murine antibodies in clinical studies of both fractionated RIT and combinations of imaging and therapy with the same mAb. [26][27][28][29] The Cyclosporin A treatment resulted in significantly lower concentrations of RAHA in plasma, comparable to pretreatment levels (Fig. 3).…”

Sensitization of tumour cells to lysis by virus-specific CTL using antibody-targeted MHC class I/peptide complexes

“…Nevertheless, it is apparent that multi-layer antibody-avidin delivery systems are viable in clinical research (Magnani et al, 1995), with the high affinity (10 -15 M) non-covalent bond formed between biotin and avidin being exploited in antibody targeting systems to deliver effector mechanisms including radioactive isotopes (Paganelli et al, 1991) and tumour necrosis factor (Moro et al, 1997). The immunogenicity of avidin or other components of the targeting system may limit repeated use; however, such responses might be minimized by transient immunosuppression (Ledermann et al, 1991). Alternative less immunogenic two-step delivery systems, such as the recently described calmodulincalmodulin binding peptide system (Neri et al, 1996), may also become available clinically.…”