Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival.

Abstract

<b>Purpose:</b> Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.<b>Patients and Methods:</b> Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T-induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8⁺ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples.<b>Results:</b> Increased PA2024-specific CD4⁺ (<i>P</i> = 0.030) and CD8⁺ (<i>P</i> = 0.052) T-cell proliferation from baseline to week 6 was observed (<i>N</i> = 14) post-sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (<i>P</i> < 0.0001; <i>N</i> = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson <i>R</i>, 0.52; <i>P</i> = 0.013) or PA2024 (Pearson <i>R</i>, 0.67; <i>P</i> = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (<i>P</i> = 0.0005; <i>N</i> = 22), with PA2024 responses correlating with PAP responses at week 26 (<i>R</i> = 0.90; <i>P</i> = 1.53E^-08).<b>Conclusions:</b> This study is the first to report PAP-specific CD8⁺ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. <i>Clin Cancer Res; 24(19); 4662-71. ©2018 AACR</i>.