ABSTRACT
PURPOSE: We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor-targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan-Meier methodology was used to analyze survival. RESULTS: Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1-40.7) months for STAMP and 32.5 (26.0-45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458-1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639-1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed. CONCLUSIONS: Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Subject(s)
Abiraterone Acetate , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Tissue Extracts , Nitriles , Treatment OutcomeABSTRACT
Sipuleucel-T, an autologous cellular immunotherapy, was approved to treat metastatic castration-resistant prostate cancer in 2010 in the United States. Treatment with sipuleucel-T primes the immune system to target prostate acid phosphatase, which is expressed by prostate cancer cells, potentially leading to lysis of cancer cells. Expanding on previously reported indirect evidence of cell killing with sipuleucel-T treatment, we sought to provide direct evidence of cell lysis through visualization. We used advanced video technology and available samples of peripheral blood mononuclear cells from subjects enrolled in the STAMP trial (NCT01487863). Isolated CD8+ T cells were used as effector cells and cocultured with autologous monocytes pulsed with control or target antigens. Differentially stained effector and target cells were then video recorded during coculture. Here, we present video recordings and analyses of T cells from sipuleucel-T-treated subjects showing-for the first time-direct lysis of cells that express prostate cancer target antigens, prostate acid phosphatase, or prostate-specific antigen.
Subject(s)
Cancer Vaccines , Prostatic Neoplasms , Cancer Vaccines/therapeutic use , Humans , Immunotherapy , Leukocytes, Mononuclear , Male , Prostate/pathology , Prostatic Neoplasms/drug therapy , Tissue Extracts/pharmacology , Tissue Extracts/therapeutic use , United StatesABSTRACT
Sipuleucel-T is an autologous cellular immunotherapy, administered as three infusions, for metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T induces T- and B-cell responses to prostatic acid phosphatase (PAP), correlating to improved survival. The long-term impact of sipuleucel-T on tumor antigen-specific immunologic memory remains unknown, in particular, B-cell responses, as measured by antigen-specific antibody responses and B-cell receptor (BCR) sequences. To evaluate whether sipuleucel-T could induce long-term immunologic memory, we examined circulating B-cell responses before and after sipuleucel-T treatment in two groups of patients with mCRPC: those who had previously received sipuleucel-T (treated; median, 8.9 years since the previous treatment) versus those who had not (naïve). Before re-treatment, previously treated patients exhibited persistent antibody responses as well as more focused and convergent BCR repertoires with distinct V(D)J gene usage compared with naïve patients. After re-treatment, previously treated patients maintained high-frequency clones and developed more convergent BCRs at earlier time points unlike naïve patients. With the first sipuleucel-T infusion specifically, previously treated patients had less shuffling within the 100 most abundant baseline clones. In contrast, naïve patients exhibited great BCR turnover with a continued influx of new B-cell clones. Social network analysis showed that previously treated patients had more highly organized B-cell repertoires, consistent with greater clonal maturation. Higher treatment-induced BCR clonality correlated with longer survival for naïve patients. These results demonstrated the capacity of sipuleucel-T to induce long-term immune memory and lasting changes to the B-cell repertoire.
Subject(s)
B-Lymphocytes/drug effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/immunology , Tissue Extracts/therapeutic use , Acid Phosphatase/drug effects , Aged , Aged, 80 and over , Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , Humans , Immunotherapy , Male , Middle Aged , Prostatic Neoplasms, Castration-Resistant/pathology , Survival RateABSTRACT
Fecal impaction is common in elderly, bed ridden, schizoaffective patients on antipsychotics. Intestinal obstruction due to distal colonic fecaliths is rare as it is amenable to digital manual evacuation and enemas. Our patient presented with abdominal distention, with last bowel evacuation reported 3 months ago. Computed tomography (CT) abdomen demonstrated a huge sigmoid fecalith causing bilateral hydronephrosis. He was managed through laparotomy with sigmoid colon resection and end colostomy.
ABSTRACT
Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.
Subject(s)
Cancer Vaccines/therapeutic use , Prostatic Neoplasms/therapy , Tissue Extracts/therapeutic use , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Humans , Male , Prostatic Neoplasms/immunology , Randomized Controlled Trials as TopicABSTRACT
PURPOSE: African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T. PATIENTS AND METHODS: OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races. CONCLUSION: In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.
Subject(s)
Black or African American/statistics & numerical data , Cancer Vaccines/administration & dosage , Health Status Disparities , Prostatic Neoplasms, Castration-Resistant/therapy , Tissue Extracts/administration & dosage , White People/statistics & numerical data , Adult , Aged , Aged, 80 and over , Disease Progression , Follow-Up Studies , Humans , Infusions, Intravenous , Kallikreins/blood , Kaplan-Meier Estimate , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Registries/statistics & numerical data , Time Factors , Treatment OutcomeABSTRACT
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
Background Awareness during general anesthesia is undesired and unanticipated patient wakefulness during surgery or recall of intraoperative events. Incidence of awareness in patients undergoing cardiac surgery is significantly higher than the overall incidence of 1% during general surgery. Awareness during cardiac surgery can be prevented by a number of methods. One such method is the supplemental, intraoperative use of sedative agents. Propofol, a bisubstituted phenol, is an intravenous general anesthetic that has been shown to reduce the incidence of awareness. Dexmedetomidine-an alpha2-adrenergic agonist with anxiolytic, opioid, and general anesthetic-sparing properties-is being considered for maintaining intraoperative depth of anesthesia. The purpose of this study was to evaluate the effect of dexmedetomidine on depth of anesthesia and to compare it with the effect of propofol in cardiac surgery. Methods This was a prospective, randomized, double-blind study conducted in a tertiary-care hospital. Sixty patients with American Society of Anesthesiologists (ASA) physical status I-III planned for elective open heart surgery were randomized into two groups of 30 patients each. Each patient of the dexmedetomidine group received an initial loading dose of dexmedetomidine at 1 mcg kg-1 over 10 minutes followed by infusion at the rate of 0.2-0.6 mcg kg-1 hr-1. Patients of the propofol group received propofol infusion at the rate of 0.25-1 mg kg-1 hr-1. An identical technique-of standard general anesthesia and routine physiological monitoring-was used in both groups. Bispectral scores were recorded at predetermined intervals during surgery and the target bispectral index (BIS) was kept at 50±10. The patients were assessed for awareness and recall 24 hours after tracheal extubation using the Brice Questionnaire. Results Intraoperative BIS scores remained within the target range in both groups; however, the BIS scores showed variable trends between the groups and were significantly lower in the dexmedetomidine group (p < 0.001). None of the patients in either group had recall of intraoperative events. Conclusion Administration of dexmedetomidine was as effective in reducing awareness and recall in cardiac surgery compared to propofol. Thus, dexmedetomidine can be used as an alternative sedative agent to prevent awareness and recall in cardiac surgery.
ABSTRACT
Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes.
Subject(s)
Antigens, Neoplasm/immunology , Immunotherapy , Neoplasms/immunology , Neoplasms/therapy , Antigen Presentation , Humans , Immunity, Cellular , Immunity, Humoral , Time FactorsABSTRACT
Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-TâADT versus ADTâsipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-TâADT versus ADTâsipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P = 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P = 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-TâADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 23(10); 2451-9. ©2016 AACR.
Subject(s)
Androgens/metabolism , Cancer Vaccines/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Prostatic Neoplasms/drug therapy , Tissue Extracts/administration & dosage , Aged , Aged, 80 and over , Androgen Antagonists/administration & dosage , Androgen Antagonists/immunology , Cancer Vaccines/immunology , Humans , Immunotherapy , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Middle Aged , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prostate-Specific Antigen/blood , Prostatic Neoplasms/genetics , Prostatic Neoplasms/immunology , Prostatic Neoplasms/pathology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tissue Extracts/immunologyABSTRACT
PURPOSE: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. EXPERIMENTAL DESIGN: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. RESULTS: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. CONCLUSIONS: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Abiraterone Acetate/administration & dosage , Aged , Aged, 80 and over , Antigen-Presenting Cells/immunology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Lymphocyte Activation/immunology , Lymphocyte Count , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Prednisone/administration & dosage , Prostatic Neoplasms, Castration-Resistant/mortality , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tissue Extracts/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: Antitumor activity of cancer immunotherapies may elicit immune responses to nontargeted (secondary) tumor antigens, or antigen spread. We evaluated humoral antigen spread after treatment with sipuleucel-T, an immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), designed to target prostatic acid phosphatase (PAP; primary antigen). EXPERIMENTAL DESIGN: Serum samples from patients with mCRPC enrolled in the placebo-controlled phase III IMPACT study (evaluable n = 142) were used to assess humoral antigen spread after treatment with sipuleucel-T. Immunoglobulin G (IgG) responses to self-antigens (including tumor antigens) were surveyed using protein microarrays and confirmed using Luminex xMAP. IgG responses were subsequently validated in ProACT (n = 33), an independent phase II study of sipuleucel-T. Association of IgG responses with overall survival (OS) was assessed using multivariate Cox models adjusted for baseline prostate-specific antigen (PSA) and lactate dehydrogenase levels. RESULTS: In patients from IMPACT and ProACT, levels of IgG against multiple secondary antigens, including PSA, KLK2/hK2, K-Ras, E-Ras, LGALS8/PCTA-1/galectin-8, and LGALS3/galectin-3, were elevated after treatment with sipuleucel-T (P < 0.01), but not control. IgG responses (≥ 2-fold elevation posttreatment) occurred in ≥ 25% of patients, appeared by 2 weeks after sipuleucel-T treatment, and persisted for up to 6 months. IgG responses to PSA and LGALS3 were associated with improved OS in sipuleucel-T-treated patients from IMPACT (P ≤ 0.05). CONCLUSIONS: Sipuleucel-T induced humoral antigen spread in patients with mCRPC. IgG responses were associated with improved OS in IMPACT. The methods and results reported may identify pharmacodynamic biomarkers of clinical outcome after sipuleucel-T treatment, and help in clinical assessments of other cancer immunotherapies. See related commentary by Hellstrom and Hellstrom, p. 3581.
Subject(s)
Antigens, Neoplasm/blood , Immunity, Humoral/immunology , Immunoglobulin G/blood , Prostatic Neoplasms, Castration-Resistant/blood , Aged , Antigens, Neoplasm/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Humans , Immunoglobulin G/immunology , Immunotherapy , Kaplan-Meier Estimate , Male , Middle Aged , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/immunology , Tissue Extracts/administration & dosage , Tissue Extracts/pharmacokineticsABSTRACT
Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥ 1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival [HR, 0.713; 95% confidence interval (CI), 0.525-0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563-1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.
Subject(s)
Cancer Vaccines/therapeutic use , Eosinophils/immunology , Prostatic Neoplasms, Castration-Resistant/therapy , Tissue Extracts/therapeutic use , Adult , Aged , Aged, 80 and over , Blood Proteins/metabolism , Bone Neoplasms/immunology , Bone Neoplasms/secondary , Bone Neoplasms/therapy , Cancer Vaccines/immunology , Double-Blind Method , Humans , Kaplan-Meier Estimate , Leukocyte Count , Male , Middle Aged , Prognosis , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/immunology , Retrospective Studies , Tissue Extracts/immunology , Treatment OutcomeABSTRACT
BACKGROUND: Sipuleucel-T is a US Food and Drug Administration-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting. METHODS: Patients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order. RESULTS: Of the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon-γ responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3(+), CD4(+) FOXP3(-), and CD8(+) T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P < .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1(+) and Ki-67(+), consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman's rank order correlation. CONCLUSIONS: This study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment.
Subject(s)
Cancer Vaccines/therapeutic use , Immunotherapy/methods , Interferon-gamma/drug effects , Lymphocyte Activation/drug effects , Neoadjuvant Therapy/methods , Prostatectomy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/immunology , T-Lymphocytes/drug effects , Tissue Extracts/therapeutic use , Aged , CD3 Complex/drug effects , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Cancer Vaccines/administration & dosage , Cancer Vaccines/adverse effects , Forkhead Transcription Factors/drug effects , Humans , Immunohistochemistry , Interferon-gamma/immunology , Lymphocyte Activation/immunology , Male , Middle Aged , Prospective Studies , Prostatectomy/methods , Prostatic Neoplasms, Castration-Resistant/pathology , Prostatic Neoplasms, Castration-Resistant/surgery , T-Lymphocytes/immunology , Tissue Extracts/administration & dosage , Tissue Extracts/adverse effects , Treatment Outcome , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunologyABSTRACT
Immunotherapies are coming to the forefront as a treatment paradigm in cancer with multiple US FDA approvals in recent years and a better understanding of their therapeutic mode of action. The control of tumor growth by the immune system is orchestrated by a complex array of cellular interactions and molecular pathways, both in the immune cells as well as the tumor. Although research over the past three decades has elucidated many aspects of tumor immunosurveillance, given the inherent complexity of the immune cell phenotypes and function, high-throughput molecular profiling ('omics') approaches have now become essential to support the discovery and development of new therapies. Technologies, such as DNA and protein microarrays, deep sequencing, mass spectrometry, as well as the computational methods for their analyses, are advancing the contributions of systems biology towards the development and mechanistic understanding of cancer immunotherapies. In this review, the authors illustrate this through some recently reported studies.
Subject(s)
Biomarkers, Tumor/metabolism , Immunotherapy , Molecular Targeted Therapy , Neoplasms/therapy , Systems Biology , Animals , Drug Discovery , Genomics , High-Throughput Screening Assays , Humans , Immunotherapy/methods , Neoplasms/diagnosis , Neoplasms/genetics , Neoplasms/immunology , Neoplasms/metabolism , Predictive Value of Tests , Treatment OutcomeABSTRACT
PURPOSE: Sipuleucel-T, the first FDA-approved autologous cellular immunotherapy for treatment of advanced prostate cancer, is manufactured by activating peripheral blood mononuclear cells, including antigen presenting cells (APCs), with a fusion protein containing prostatic acid phosphatase. Analysis of data from three phase 3 trials was performed to immunologically characterize this therapy during the course of the three doses, and to relate the immunological responses to overall survival (OS). METHODS: Sipuleucel-T product characteristics [APC numbers, APC activation (CD54 upregulation), and total nucleated cell (TNC) numbers] were assessed in three randomized, controlled phase 3 studies (N = 737). Antigen-specific cellular and humoral responses were assessed in a subset of subjects. The relationships between these parameters and OS were assessed. RESULTS: APC activation occurred in the first dose preparation [6.2-fold, (4.65, 7.70); median (25th, 75th percentile)] and increased in the second [10.6-fold (7.83, 13.65)] and third [10.5-fold (7.89, 13.65)] dose preparations. Cytokines and chemokines associated with activated APCs were produced during the manufacture of each dose; T-cell activation-associated cytokines were detected in the second and third dose preparations. Antigen-specific T cells were detectable after administration of the first sipuleucel-T dose. Cumulative APC activation, APC number, and TNC number correlated with OS (P < 0.05). Antigen-specific immune responses were observed in 78.8 % of monitored subjects and their presence correlated with OS (P = 0.003). CONCLUSION: Sipuleucel-T broadly engages the immune system by activating APCs ex vivo and inducing long-lived immune responses in vivo. These data indicate antigen-specific immune activation as a mechanism by which sipuleucel-T prolongs OS.
Subject(s)
Orchiectomy , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , T-Lymphocytes/immunology , Tissue Extracts/immunology , Tissue Extracts/therapeutic use , Aged , Aged, 80 and over , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Chemokines/biosynthesis , Chemokines/immunology , Double-Blind Method , Humans , Kaplan-Meier Estimate , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Male , Middle Aged , Proportional Hazards Models , Prostatic Neoplasms/mortality , T-Lymphocytes/metabolismABSTRACT
Although vaccine adjuvants have been used for almost a century, alum is the only adjuvant licensed by the US FDA for human vaccine use. Many adjuvants studied to date have generalized inflammatory properties and lack specificity in terms of targeting immune compartments and cell populations. Indeed, such adjuvants have often been crude in formulation, their effects usually restricted to T-helper 2-type immunity and their use limited owing to inherent toxicity. However, recent advances in immunology have resulted in a number of potential adjuvant candidates that are able to modulate the immune response in a more controlled and specific manner. These novel adjuvants are attractive for inclusion in current and future vaccine strategies since they have better-defined mechanisms of action. In this article, we review several compounds that target specific immune components, such as cells, receptors or signaling pathways, and have termed such reagents 'smart adjuvants'.
Subject(s)
Adjuvants, Immunologic , Vaccines/immunology , Animals , Cytokines/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Humans , Receptors, Pattern Recognition/immunology , Toll-Like Receptors/immunologyABSTRACT
A major drawback of subunit vaccines is their inability to generate cytolytic T lymphocytes (CTL), a deficit attributed to segregation of the class I and class II antigen-processing pathways. We sought to understand processes involved in CTL induction by three proprietary adjuvants: Tomatine, PROVAX, and a synthesized glycolipid (Glc-N-(8/16), Glycolipid). We used in vivo models to investigate antigen uptake, macrophage involvement, TAP-independent processing, and costimulatory molecule dependencies. Glycolipid required splenic and lymph node macrophages, whereas Tomatine generated CTL independently of either macrophage population. In contrast, PROVAX showed partial macrophage requirements. Immunized TAP knockout mice revealed that ovalbumin (OVA)-Tomatine and OVA-PROVAX, but not OVA-Glycolipid, generate class I-peptide complexes. All three immunostimulants also elicited CD86-dependent TH1 cytokine responses.
Subject(s)
Adenomatous Polyposis Coli Protein/immunology , Adjuvants, Immunologic/pharmacology , Antigen Presentation/immunology , Antigens, CD/immunology , Membrane Glycoproteins/immunology , T-Lymphocytes, Cytotoxic/physiology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Antigens/immunology , B7-2 Antigen , Captopril/pharmacology , Chemistry, Pharmaceutical , Cytokines/biosynthesis , Endoplasmic Reticulum/enzymology , Female , Flow Cytometry , Macrophages/immunology , Macrophages/physiology , Mice , Mice, Inbred C57BL , Ovalbumin/immunology , Peptides/immunology , Peptidyl-Dipeptidase A/physiology , Phagocytosis/drug effects , Phagocytosis/physiology , T-Lymphocytes, Cytotoxic/drug effectsABSTRACT
The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.