Potentiation of antitumor immunity by antibody-directed enzyme prodrug therapy

Anti body-directed enzyme prodrug therapy (ADEPT) has displayed antitumor a ctivity in animal models and clinical trials. We examined whether antitumor immunity is generated during ADEPT by employing an immunoenzyme composed o f the monoclonal antibody (MAb) RH1 conjugated to beta -glucuronidase to ta rget rat AS-30D hepatocellular carcinoma tumors. A glucuronide prodrug of p -hydroxyaniline mustard was used to treat malignant ascites after immunoenz yme localization at the cancer cells. ADEPT cured more than 96% of Sprague- Dawley rats bearing advanced malignant ascites, and all cured rats were pro tected from a lethal challenge of AS-30D cells. Immunization with radiation -killed AS-30D cells or AS-30D cells coated with immunoenzyme did not provi de tumor protection. Likewise, ex vivo treatment of tumor cells by ADEPT be fore injection into rats did not protect against a tumor challenge. AS-30D and NI-SI hepatocellular carcinoma cells but not unrelated syngeneic tumor cells were lysed by peritoneal exudate cells isolated from ADEPT-cured rats . Depletion of CD8(+) but not CD4(+) T cells or natural killer (NK) cells r educed the cytolytic activity of peritoneal lymphocytes. ADEPT did not cure tumor-bearing rats depleted of CD4(+) and CD8+ T cells even though it was curative when given 7 days after tumor transplantation in rats with an inta ct immune system, indicating that ADEPT can synergize with host immunity to increase therapeutic efficacy. These results have important implications f or the clinical application of ADEPT. (C) 2001 Wiley-Liss, Inc.