title: Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells.
abstract: OBJECTIVE
  Tremelimumab is a fully human monoclonal antibody specific for CTL-associated antigen 4 (CTLA4) with single-agent activity in certain tumors but has not been evaluated in patients with breast cancer.
  
  
  METHODS
  In a phase 1 study, 26 patients with advanced, hormone-responsive breast cancer received tremelimumab (3-10 mg/kg) every 28 days or every 90 days plus exemestane 25 mg daily. The objectives were to determine safety and the maximum tolerated dose (MTD) of tremelimumab with exemestane and, secondarily, to assess tumor response, pharmacokinetics, and immune pharmacodynamics.
  
  
  RESULTS
  Most treatment-related adverse events were mild to moderate with the most common being diarrhea (46% of patients), pruritus (42%), constipation (23%), and fatigue (23%). Dose-limiting toxicities were transient serum transaminase elevations (one patient) and diarrhea (four patients). The MTD of tremelimumab with exemestane was 6 mg/kg every 90 days. Among 13 patients treated at the MTD, none developed grade 3 or 4 treatment-related diarrhea. No pharmacokinetic interaction was observed between tremelimumab and exemestane. The best overall response was stable disease for >or=12 weeks in 11 patients (42%). Treatment was associated in most patients with increased peripheral CD4+ and CD8+ T cells expressing inducible costimulator (ICOS) and a marked increase in the ratio of ICOS+ T cells to FoxP3+ regulatory T cells.
  
  
  CONCLUSIONS
  Tremelimumab plus exemestane is tolerable in patients with hormone-responsive advanced breast cancer. Treatment is associated with increased ICOS+ T cells, which likely signals immune activation secondary to CTL-associated antigen 4 blockade.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.forename: Magi
authors.initials: M
authors.lastname: Khalil
authors.forename: Elaina M
authors.initials: EM
authors.lastname: Gartner
authors.forename: Divis
authors.initials: D
authors.lastname: Khaira
authors.forename: Denis
authors.initials: D
authors.lastname: Soulieres
authors.forename: Prudence
authors.initials: P
authors.lastname: Dorazio
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Trosko
authors.forename: Jens
authors.initials: J
authors.lastname: Rüter
authors.forename: Gabriella L
authors.initials: GL
authors.lastname: Mariani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Usari
authors.forename: Susan M
authors.initials: SM
authors.lastname: Domchek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; C056516:exemestane; C520704:tremelimumab