title: CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans.
abstract: BACKGROUND
  CTLA4 blocking monoclonal antibodies provide durable clinical benefit in a subset of patients with advanced melanoma mediated by intratumoral lymphocytic infiltrates. A key question is defining whether the intratumoral infiltration (ITI) is a differentiating factor between patients with and without tumor responses.
  
  
  METHODS
  Paired baseline and postdosing tumor biopsy specimens were prospectively collected from 19 patients with metastatic melanoma, including 3 patients with an objective tumor response, receiving the anti-CTLA4 antibody tremelimumab within a clinical trial with primary endpoint of quantitating CD8(+) cytotoxic T-lymphocyte (CTL) infiltration in tumors. Samples were analyzed for cell density by automated imaging capture and further characterized for functional lymphocyte properties by assessing the cell activation markers HLA-DR and CD45RO, the cell proliferation marker Ki67, and the regulatory T-cell marker FOXP3.
  
  
  RESULTS
  There was a highly significant increase in ITI by CD8(+) cells in biopsy samples taken after tremelimumab treatment. This included increases between 1-fold and 100-fold changes in 14 of 18 evaluable cases regardless of clinical tumor response or progression. There was no difference between the absolute number, location, or cell density of infiltrating cells between clinical responders and patients with nonresponding lesions that showed acquired intratumoral infiltrates. There were similar levels of expression of T-cell activation markers (CD45RO, HLA-DR) in both groups and no difference in markers for cell replication (Ki67) or the suppressor cell marker FOXP3.
  
  
  CONCLUSIONS
  CTLA4 blockade induces frequent increases in ITI by T cells despite which only a minority of patients have objective tumor responses.
authors.affiliation: Division of Hematology-Oncology, 11-934 Factor Building, UCLA Medical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
authors.forename: Rong Rong
authors.initials: RR
authors.lastname: Huang
authors.forename: Jason
authors.initials: J
authors.lastname: Jalil
authors.forename: James S
authors.initials: JS
authors.lastname: Economou
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Stephen
authors.initials: S
authors.lastname: Mok
authors.forename: Hooman
authors.initials: H
authors.lastname: Sazegar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seja
authors.forename: Arturo
authors.initials: A
authors.lastname: Villanueva
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomez-Navarro
authors.forename: John A
authors.initials: JA
authors.lastname: Glaspy
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology*; D001706:Biopsy; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab