Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer

Cancer Immunol Immunother. 2013 Jan;62(1):137-47. doi: 10.1007/s00262-012-1317-2. Epub 2012 Aug 3.

Abstract

Purpose: 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).

Conclusion: 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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Chemokines / biosynthesis
  • Chemokines / immunology
  • Double-Blind Method
  • Humans
  • Kaplan-Meier Estimate
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Middle Aged
  • Orchiectomy*
  • Proportional Hazards Models
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / therapy*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tissue Extracts / immunology*
  • Tissue Extracts / therapeutic use*

Substances

  • Chemokines
  • Tissue Extracts
  • sipuleucel-T