title: Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
abstract: OBJECTIVE
  Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.
  
  
  METHODS
  Six patients were treated with 3 mg/kg/dose of anti-CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.
  
  
  RESULTS
  Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.
  
  
  CONCLUSIONS
  Our trial shows that anti-CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Bradley C
authors.initials: BC
authors.lastname: Carthon
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Ashish
authors.initials: A
authors.lastname: Kamat
authors.forename: Derek S
authors.initials: DS
authors.lastname: Ng Tang
authors.forename: Jingjing
authors.initials: J
authors.lastname: Sun
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Ku
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D013519:Urogenital Surgical Procedures
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab
references.citation: Cancer Immun. 2008 May 27;8:9
references.pmid: 18503261
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1810-5
references.pmid: 17363537
references.citation: Curr Opin Immunol. 2010 Jun;22(3):326-32
references.pmid: 20116985
references.citation: J Exp Med. 1999 Aug 2;190(3):355-66
references.pmid: 10430624
references.citation: Nature. 1992 Apr 16;356(6370):607-9
references.pmid: 1313950
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7
references.pmid: 12826605
references.citation: Cancer Immun. 2008 Jan 17;8:1
references.pmid: 18198818
references.citation: J Exp Med. 1995 Aug 1;182(2):459-65
references.pmid: 7543139
references.citation: Clin Cancer Res. 2009 Dec 1;15(23):7412-20
references.pmid: 19934295
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2729-34
references.pmid: 19202079
references.citation: Nat Immunol. 2009 Feb;10(2):167-75
references.pmid: 19098919
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14987-92
references.pmid: 18818309
references.citation: N Engl J Med. 2009 Jul 9;361(2):211-2
references.pmid: 19587352
references.citation: J Clin Oncol. 2008 Dec 20;26(36):5950-6
references.pmid: 19018089
references.citation: Eur J Immunol. 2006 Jul;36(7):1892-903
references.pmid: 16791882
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4712-7
references.pmid: 12682289
references.citation: J Immunol. 2005 Aug 15;175(4):2340-8
references.pmid: 16081804
references.citation: Cancer Immun. 2003 Dec 18;3:19
references.pmid: 14680360
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4192-7
references.pmid: 15014176
references.citation: Curr Opin Investig Drugs. 2005 Jun;6(6):582-91
references.pmid: 15988909
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20371-6
references.pmid: 19915142
references.citation: Clin Cancer Res. 2009 Oct 15;15(20):6446-53
references.pmid: 19808874
references.citation: J Exp Med. 1996 Jun 1;183(6):2533-40
references.pmid: 8676074
references.citation: Pituitary. 2010;13(1):29-38
references.pmid: 19639414
references.citation: J Clin Invest. 2006 Jul;116(7):1935-45
references.pmid: 16778987
references.citation: Immunity. 1997 Oct;7(4):445-50
references.pmid: 9354465
references.citation: Science. 1996 Mar 22;271(5256):1734-6
references.pmid: 8596936
references.citation: J Clin Oncol. 2009 Mar 1;27(7):1075-81
references.pmid: 19139427