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 < 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 : an official journal of the American Association for Cancer Research. 2018 Jun 01 [Epub]
Emmanuel S Antonarakis, Eric J Small, Daniel P Petrylak, David I Quinn, Adam S Kibel, Nancy N Chang, Erica Dearstyne, Matt Harmon, Dwayne Campogan, Heather Haynes, Tuyen Vu, Nadeem A Sheikh, Charles G Drake
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Yale Cancer Center, New Haven, Connecticut., Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California., Dana Farber/Brigham and Women's Cancer Center, Harvard University, Boston, Massacheuttes., Dendreon Pharmaceuticals, LLC, Seattle, Washington., Columbia University Herbert Irving Comprehensive Cancer Center, Department of Urology, and the Columbia Center for Translational Immunology (CCTI), New York, New York. .