Antigen-specific CD8 lytic phenotype induced by sipuleucel-T in hormone-sensitive or castration-resistant prostate cancer and association with overall survival

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 sipuleu-cel-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^þ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples. Results: Increased PA2024-specific CD4^þ (P ¼ 0.030) and CD8^þ (P ¼ 0.052) T-cell proliferation from baseline to week 6 was observed (N ¼ 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 < 0.0001; N ¼ 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P ¼ 0.013) or PA2024 (Pearson R, 0.67; P ¼ 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P ¼ 0.0005; N ¼ 22), with PA2024 responses correlating with PAP responses at week 26 (R ¼ 0.90; P ¼ 1.53E⁰⁸). Conclusions: This study is the first to report PAP-specific CD8^þ 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.