Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.

Abstract

Immunotoxins (ITs) are potent cytotoxic agents used in the treatment of cancer, autoimmune disease, and graft-versus-host disease. Results from clinical trials demonstrate that many IT-treated patients, especially those with an intact immune system, develop anti-IT antibodies that may prohibit repeated IT dosing. We, therefore, evaluated a panel of novel immunosuppressive (IS) agents for their ability to inhibit the antitoxin immune response in mice receiving multiple courses of a ricin A chain (RTA)-containing IT and also assessed whether this suppression would result in an increase in IT-mediated antitumor activity. The results indicate that a 3-day pretreatment, plus one additional boost 2 weeks later, of a combination of hCTLA4Ig + anti-CD40L, virtually eliminated the anti-RTA response in normal mice receiving six weekly injections of an IT. When tested in BCL1 tumor-bearing mice, the concomitant use of a combination of hCTLA4Ig + anti-CD40L and six doses of the IT resulted in a 1.5-fold increase in tumor cell killing, as compared with treatment with IT alone. We conclude that a combination of IS + IT therapy should facilitate the administration of multiple courses of IT, as well as enhance its antitumor activity.