Correlation between product parameters and overall survival in three trials of sipuleucel-T, an autologous active cellular immunotherapy for the treatment of prostate cancer.

Abstract

4552 Background: Sipuleucel-T is an investigational autologous active cellular immunotherapy for treatment of metastatic castration-resistant prostate cancer (CRPC). It contains peripheral blood mononuclear cells including antigen-presenting cells (APCs), that have been incubated with a recombinant fusion protein, PA2024, comprising the antigen prostatic acid phosphatase (PAP) fused to GM-CSF. Three multicenter, randomized, double-blind, placebo-controlled trials provided evidence that sipuleucel-T prolongs overall survival (OS) in CRPC. Methods: The correlation between key product parameters and OS was assessed in patients who received ≥1 sipuleucel-T infusion (N=476) using a Cox regression model both unadjusted and adjusted for baseline prognostic variables (PSA [ln] and LDH [ln]), while stratifying by study. Parameters included CD54 upregulation, CD54+ cell count, and total nucleated cell (TNC) count. CD54 upregulation is the fold increase in the average number of CD54 molecules expressed on final product APCs. CD54 was chosen as a biologically relevant marker because of its role in the immunologic synapse between APCs and T cells, and because its increased expression correlates with APC activation. Experiments have demonstrated that CD54+ APCs take up the PA2024 antigen and present PAP epitopes to HLA-restricted PAP-specific T cell lines. The product variables analyzed represent the sum of values infused into each patient (up to 3 infusions). Results: A positive correlation (p < 0.05) was observed for each of the product parameters assessed as a continuous variable, in both the unadjusted and adjusted Cox models. Conclusions: There was a significant correlation between OS and each of the three cell product parameters, which appeared to be independent of baseline prognostic factors. These data support the conclusion that broad engagement of the immune system contributes to the sipuleucel-T survival findings. Cell product parameter P value Unadjusted (N=476) Adjusted for PSA and LDH (N=476) Cumulative TNC (x 109) < 0.001 < 0.001 Cumulative CD54+ cell count (x 109) 0.016 0.005 Cumulative CD54 upregulation 0.002 0.041 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Dendreon Dendreon Dendreon Dendreon