Eradication of established renal cell carcinoma by a combination of 5-fluorouracil and anti-4-1BB monoclonal antibody in mice.
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.
Ju
Seong-A
SA
Immunomodulation Research Center, University of Ulsan, Ulsan, Republic of Korea.
Cheon
Sang-Hyeon
SH
Park
Sang-Min
SM
Tam
Nyuen Quang
NQ
Kim
Young Min
YM
An
Won G
WG
Kim
Byung-Sam
BS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000628:therapy*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D005472:Fluorouracil