ABSTRACT
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.
Subject(s)
Neoplasms, Hormone-Dependent/drug therapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , T-Lymphocytes, Cytotoxic/drug effects , Tissue Extracts/administration & dosage , Acid Phosphatase/genetics , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Clinical Trials as Topic , Gene Expression Regulation, Neoplastic/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Humans , Lysosomal-Associated Membrane Protein 1/genetics , Lysosomal-Associated Membrane Protein 1/immunology , Male , Neoplasm Metastasis , Neoplasms, Hormone-Dependent/genetics , Neoplasms, Hormone-Dependent/immunology , Neoplasms, Hormone-Dependent/pathology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/immunology , Prostatic Neoplasms, Castration-Resistant/pathology , Recombinant Fusion Proteins/genetics , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
This paper physically and numerically models the influence of biofilms on heavy metal removal in a gravel filter. Experimental flow columns were constructed to determine the removal of Cu, Pb and Zn by gabbro and dolomite gravel lithologies with and without natural biofilm from sustainable urban drainage systems (SuDS). Breakthrough experiments showed that, whilst abiotic gravel filters removed up to 51% of metals, those with biofilms enhanced heavy metal removal by up to a further 29%, with Cu removal illustrating the greatest response to biofilm growth. An advection-diffusion equation successfully modelled metal tracer transport within biofilm columns. This model yielded a permanent loss term (k) for metal tracers of between 0.01 and 1.05, correlating well with measured data from breakthrough experiments. Additional 16S rRNA clone library analysis of the biofilm indicated strong sensitivity of bacterial community composition to the lithology of the filter medium, with gabbro filters displaying Proteobacteria dominance (54%) and dolomite columns showing Cyanobacteria dominance (47%).
