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Purpose: 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. Patients and Methods: 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. Results: Increased PA2024-specific CD4 + ( P = 0.030) and CD8 + ( P = 0.052) T-cell proliferation from baseline to week 6 was observed ( N = 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 ( P &lt; 0.0001; N = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R , 0.52; P = 0.013) or PA2024 (Pearson R , 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis ( P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 ( R = 0.90; P = 1.53E -08 ). Conclusions: 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. Clin Cancer Res; 24(19); 4662-71. ©2018 AACR .

clinical cancer research

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