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Combination Therapy with Cisplatin and Anti–4-1BB: Synergistic Anticancer Effects and Amelioration of Cisplatin-Induced Nephrotoxicity

¹ Division of Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Goyang, Kyeonggi-do, Korea; ² Immunomodulation Research Center, University of Ulsan, Ulsan, Korea; and ³ LSU Eye Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Requests for reprints: Byoung S. Kwon, Division of Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, 111 Jungbalsan-ro, Ilsan, Goyang, Kyeonggi-do, Korea 410-769. Phone: 82-31-920-2531; Fax: 82-31-920-2542; E-mail: bskwon{at}ncc.re.kr.

Key Words: 4-1BB • chemotherapy • nephrotoxicity

Anti–4-1BB and cisplatin showed synergistic anticancer effects in the CT-26 colon carcinoma model, producing complete regression in >60% of mice with either preventive or therapeutic treatment. The tumor-free mice formed long-lasting CD8⁺ T cell–dependent tumor-specific memory. Anti–4-1BB induced rapid repopulation of T and B cells from cisplatin-mediated lymphopenia and differentiation and expansion of IFN-⁺CD11c⁺CD8⁺ T cells. Cisplatin facilitated expansion of naïve, effector, and memory CD8⁺ T cells; combination therapy produced almost twice as many lymphoid cells as anti–4-1BB alone. Cisplatin increased 4-1BB on antigen-primed T cells and induced 4-1BB de novo on kidney tubular epithelium. Cross-linking of 4-1BB protected the T cells and kidney epithelium from cisplatin-mediated apoptosis by increasing expression of antiapoptotic molecules. Thus, cisplatin-induced 4-1BB provided a mechanism for amelioration of the lymphopenia and nephrotoxicity inherent in cisplatin treatment. We concluded that chemoimmunotherapy with anti–4-1BB and cisplatin is synergistic in tumor killing and prevention of organ-specific toxicity. [Cancer Res 2008;68(18):7264–9]