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

Abstract

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. 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. Increased PA2024-specific CD4 ( = 0.030) and CD8 ( = 0.052) T-cell proliferation from baseline to week 6 was observed ( = 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 ( < 0.0001; = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson, 0.52; = 0.013) or PA2024 (Pearson, 0.67; = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis ( = 0.0005; = 22), with PA2024 responses correlating with PAP responses at week 26 ( = 0.90; = 1.53E). 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. .

Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry

“…Sipuleucel-T is designed to activate the immune system against the prostatic acid phosphatase expressed on most prostate cancer cells. Sipuleucel-T-induced antigen-specific cellular and humoral immune responses correlate with OS [28,29]. Thus, immunological differences could be one factor leading to greater OS benefit for African Americans with an immunotherapy.…”

Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine

“…Unlike the present strategy, cancer vaccines or immunotherapies based on tumor antigens, dendritic cells, or immune-checkpoint antibodies require positive MHC-I surface expression on tumor cells to be effective [54]. For instance, the sole FDA-approved cancer vaccine is only effective when prostate tumor cells express MHC-I [55]. Hence, our anticancer vaccine may be a useful approach before the initiation of other immunotherapies and may even act as a personalized anti-tumor immunotherapeutic vaccine.…”

Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities

“…Provenge (sipuleucel-T) has demonstrated statistically significant associations of antigen-specific CD8 + T cell responses with overall survival in patients with metastatic castration-resistant prostate cancer and is the only US Food and Drug Administration (FDA)-approved TCV. 120,121 A quantitative analysis across 451 clinical trials of TCVs from 1999 to 2014 indicated a lack of consistency in TCV approaches with no clear benefit of any particular adjuvant or platform to induce immune or objective responses. 5 Despite evidence of immunological activity, many TCVs tested failed to reveal correlations between vaccine-induced immunity and clinical benefit.…”