Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced 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-gamma(+)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.
Kim
Young H
YH
Division of Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Goyang, Kyeonggi-do, Korea.
Choi
Beom K
BK
Kim
Kwang H
KH
Kang
Sang W
SW
Kwon
Byoung S
BS
D053330:4-1BB Ligand / Q000819:agonists / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004357:Drug Synergism; D007156:Immunologic Memory / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D002945:Cisplatin
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