Renal cell carcinoma (RCC), one of the most incurable
malignancies, is highly resistant to
chemotherapy and
radiotherapy.
Cytokine immunotherapy has been the standard approach, but the overall response rate is still very low. Administration of agonistic anti-4-1BB
monoclonal antibody (mAb) has been shown to induce regression of several animal
tumors but its effect on RCC is unknown. We show here that monotherapy with either anti-4-1BB mAb or the cytotoxic drug,
5-fluorouracil (5-FU), has little effect on established RCC, Renca
tumors, but combination
therapy with anti-4-1BB mAb and
5-FU eradicates the
tumors in more than 70 % of mice. The regressing
tumor tissues from mice receiving the combination
therapy contained more apoptotic
tumor cells and tumor infiltrating lymphocytes than
tumor tissues from mice receiving
5-FU or anti-4-1BB mAb monotherapy. The number of lymphocytes in the spleens and
tumor- draining lymph nodes (TDLNs) of the combination
therapy mice was greatly increased compared to that of control or
5-FU monotherapy mice. Mice that had recovered due to the combination
therapy rapidly rejected rechallenge with the
tumor, pointing to the establishment of long-lasting
tumor-specific memory. Our results indicate that targeting
tumors with
5-FU, and immune cells with 4-1BB stimulation, could be a useful strategy for treating incurable RCC.