title: Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma.
abstract: OBJECTIVE
  Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity.
  
  
  METHODS
  This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated.
  
  
  RESULTS
  Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative) lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity.
  
  
  CONCLUSIONS
  Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.
authors.affiliation: Department of Medical Oncology, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester, United Kingdom.
authors.forename: Christy
authors.initials: C
authors.lastname: Ralph
authors.forename: Eyad
authors.initials: E
authors.lastname: Elkord
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burt
authors.forename: Jackie F
authors.initials: JF
authors.lastname: O'Dwyer
authors.forename: Eric B
authors.initials: EB
authors.lastname: Austin
authors.forename: Peter L
authors.initials: PL
authors.lastname: Stern
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Thistlethwaite
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D060908:CTLA-4 Antigen; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab