title: Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer.
abstract: OBJECTIVE
  Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS).
  
  
  METHODS
  Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed.
  
  
  RESULTS
  APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS (P = 0.003).
  
  
  CONCLUSIONS
  Sipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS.
authors.affiliation: Dendreon Corporation, Seattle, WA 98102-3703, USA. nsheikh@dendreon.com
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Sheikh
authors.forename: Daniel
authors.initials: D
authors.lastname: Petrylak
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.forename: Corazon
authors.initials: C
authors.lastname: Dela Rosa
authors.forename: Frances P
authors.initials: FP
authors.lastname: Stewart
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Kuan
authors.forename: James B
authors.initials: JB
authors.lastname: Whitmore
authors.forename: James B
authors.initials: JB
authors.lastname: Trager
authors.forename: Christian H
authors.initials: CH
authors.lastname: Poehlein
authors.forename: Mark W
authors.initials: MW
authors.lastname: Frohlich
authors.forename: David L
authors.initials: DL
authors.lastname: Urdal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology; D004311:Double-Blind Method; D006801:Humans; D053208:Kaplan-Meier Estimate; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014020:Tissue Extracts / Q000276:immunology* / Q000627:therapeutic use*
chemical_list: D018925:Chemokines; D014020:Tissue Extracts; C511774:sipuleucel-T