Effect of immunosuppressive agents on the immunogenicity and efficacy of an immunotoxin in mice.
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.
Gelber
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Department of Microbiology, The Cancer Immunobiology Center, The University of Texas Southwestern Medical Center, Dallas 75235-8576, USA.
Vitetta
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D000818:Animals; D000906:Antibodies / Q000032:analysis / Q000187:drug effects*; D005260:Female; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology*; D000922:Immunotoxins / Q000276:immunology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D012276:Ricin / Q000187:drug effects* / Q000276:immunology
D000906:Antibodies; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D012276:Ricin