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.