title: Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity.
abstract: 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.
authors.affiliation: Division of Cell and Immunobiology, and R&D Center for Cancer Therapeutics, National Cancer Center, Ilsan, Goyang, Kyeonggi-do, Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.forename: Sang W
authors.initials: SW
authors.lastname: Kang
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: 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
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D002945:Cisplatin
references.citation: Science. 2002 Oct 25;298(5594):850-4
references.pmid: 12242449
references.citation: Cell Immunol. 2003 Jun;223(2):143-50
references.pmid: 14527512
references.citation: Cancer Res. 2001 Mar 1;61(5):2031-7
references.pmid: 11280763
references.citation: Br J Cancer. 1993 Sep;68(3):469-74
references.pmid: 8353037
references.citation: Cancer Res. 2003 Aug 1;63(15):4490-6
references.pmid: 12907622
references.citation: Cancer Res. 2007 Sep 15;67(18):8891-9
references.pmid: 17875731
references.citation: Blood. 1995 Feb 15;85(4):1043-52
references.pmid: 7849293
references.citation: Kidney Int. 2007 Jul;72(1):53-62
references.pmid: 17410096
references.citation: Immunology. 2002 Dec;107(4):472-9
references.pmid: 12460192
references.citation: J Clin Invest. 2002 Sep;110(6):743-5
references.pmid: 12235103
references.citation: Cell Biol Int. 2002;26(3):271-8
references.pmid: 11991655
references.citation: Nat Rev Cancer. 2005 May;5(5):397-405
references.pmid: 15864281
references.citation: Cancer Immunol Immunother. 2001 Nov;50(9):445-55
references.pmid: 11761438
references.citation: Eur J Immunol. 2004 Feb;34(2):336-44
references.pmid: 14768038
references.citation: J Clin Invest. 2002 Mar;109(5):651-9
references.pmid: 11877473
references.citation: J Immunol. 2003 May 15;170(10):4905-13
references.pmid: 12734333
references.citation: Eur J Cancer. 1998 Sep;34(10):1522-34
references.pmid: 9893623
references.citation: J Immunol. 2002 Nov 1;169(9):4882-8
references.pmid: 12391199
references.citation: Am J Kidney Dis. 1986 Nov;8(5):368-79
references.pmid: 3538860