sipuleucel-T Infusion Research Articles

Acute ST Elevation Myocardial Infarction Following an Initial Sipuleucel-T Infusion for Castration Resistant Prostate Cancer

Sipuleucel-T is a therapeutic cancer vaccine used in patients with metastatic castration resistant prostate cancer. We describe a case of acute ST elevation myocardial infarction in a patient with metastatic prostate cancer receiving his first Sipuleucel-T infusion.

Long-term Sculpting of the B-cell Repertoire following Cancer Immunotherapy in Patients Treated with Sipuleucel-T.

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.

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

PurposeAfrican 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 methodsOS 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.ResultsMedian 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.ConclusionIn 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.

Adverse Events Associated With the Use of Sipuleucel-T Reported to the US Food and Drug Administration’s Adverse Event Reporting System, 2010-2017

Sipuleucel-T was the first therapeutic cancer vaccine approved by the US Food and Drug Administration (FDA) in 2010. Although almost a decade has passed since its approval for the treatment of asymptomatic or minimally symptomatic castration-resistant prostate cancer (CRPC), there remains a paucity of literature describing safety data in the postmarketing period. To describe the postmarketing safety experience for sipuleucel-T. In this case series study, US reports for sipuleucel-T submitted to the FDA's Adverse Event Reporting System were searched and reviewed between April 29, 2010, and December 31, 2017. This system is a spontaneous safety surveillance database for drug and therapeutic biologic products. The analysis of 3216 reports and select case reviews were undertaken between February and November 2018. Descriptive statistics were used to assess adverse event reports for sipuleucel-T. Empirical Bayes Geometric Means (EBGM) and their 90% confidence intervals (CIs) were computed to identify disproportionate (ie, at least twice the expected) reporting of sipuleucel-T-event pairs. Selected adverse events and death reports were individually reviewed. In total, 3216 reports were identified for sipuleucel-T, of which 2014 (62.6%) were serious. For all included reports, the patients' median (interquartile range) age was 73 (67-79) years, and 3149 were specified to be males. Chills (n = 318), malaise (n = 196), pyrexia (n = 189), culture positive (n = 184), fatigue (n = 180), and nausea (n = 173) were among the most commonly reported adverse events. Infusion-related reactions (EBGM, 12.1; 90% CI, 9.4-15.3), infections, vascular events, and transient ischemic attacks (EBGM, 2.9; 90% CI, 2.2-3.9) were reported disproportionately. Among 249 deaths for which relevant dates were available, 128 (51.4%) were reported within 30 days of a sipuleucel-T infusion, of which 81.2% included a specified cause of death; of these 104 deaths, there were 37 neoplasms (35.6%), 25 cardiac disorders (24.0%), 18 nervous system disorders (17.3%), and 9 infections (8.7%). Reported adverse events were generally consistent with the safety experience observed in prelicensure studies and described in the sipuleucel-T package insert. Off-label use among overtly symptomatic men with CRPC, reporting bias, or lack of product effectiveness may have influenced the reporting of deaths within 30 days of treatment initiation. With this overview of sipuleucel-T experience, the present study serves as a resource for health care professionals and patients as they weigh the risks and benefits of treatment in the context of all available therapeutic options for CRPC.

Overall survival (OS) of African-American (AA) and Caucasian (CAU) men who received sipuleucel-T for metastatic castration-resistant prostate cancer (mCRPC): Final PROCEED analysis.

5035 Background: Prostate cancer risk and mortality are higher in AAs versus CAUs. Post-hoc analyses of pooled Phase 3 data (n = 737) suggested substantial OS benefit for AA men receiving sipuleucel-T (n = 33) vs placebo (n = 10) (McLeod 2012). Compared with pooled placebo patients (n = 249), number needed to treat for OS benefit at 3 years was 3 for AAs and 8 for all sipuleucel-T-treated patients (n = 488) (Moses 2019). Herein we analyzed PROCEED (NCT01306890), a large real-world registry, in which all patients received sipuleucel-T. Methods: In PROCEED, 1902 mCRPC patients received ≥1 sipuleucel-T infusion. OS of all AA (n = 221) and CAU (n = 1649) men were compared. Baseline prostate-specific antigen (PSA), the most important prognostic variable for OS after sipuleucel-T (Schellhammer 2013), substantially differed by race. Thus, OS for a PSA-matched cohort (n = 219 AA; n = 438 CAU) was compared and univariable/multivariable analyses were performed. Post-sipuleucel-T use of OS-prolonging anticancer interventions was also assessed. Results: After a median follow-up of 46.6 mo, median OS was 35.2 (all sipuleucel-T-treated AAs) and 29.9 mo (all sipuleucel-T-treated CAUs): HR 0.81, 95% CI 0.68–0.97; P = 0.03. In the PSA-matched cohort, median OS was 35.3 and 25.8 mo, respectively (HR 0.70, 95% CI 0.57–0.86; P &lt; 0.001). Sipuleucel-T-treated AAs with lower baseline PSA had markedly longer median OS vs sipuleucel-T-treated CAUs. Among those with ≤ median baseline PSA (29.48 ng/ml), median OS was 54.3 mo (AA) vs. 33.4 (CAUs); HR 0.52, 95% CI 0.37–0.72; p &lt; 0.001. Along with other known prognostic factors, AA race was independently associated with prolonged OS on detailed multivariable analyses (HR 0.60, 95% CI 0.48–0.74; p &lt; 0.001) and confirmed on sensitivity analyses. Post-sipuleucel-T life-prolonging anti-cancer therapies were balanced between groups. Conclusions: Sipuleucel-T-treated AAs had significantly improved OS vs sipuleucel-T-treated CAUs. This analysis marks the largest known racial difference in OS in response to any therapy for mCRPC, a finding with implications for both prostate cancer pathophysiology and cancer immunotherapy. Clinical trial information: NCT01306890.

PD25-06 CHARACTERIZATION OF LONG-TERM SURVIVORS FROM PROCEED, A REGISTRY OF SIPULEUCEL-T IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER (MCRPC)

INTRODUCTION AND OBJECTIVES:PROCEED [NCT01306890], a large real-world study of sipuleucel-T in men with mCRPC, offers an opportunity to examine patients who experienced longer term (≥3 yr) survivals after receiving sipuleucel-T. The current analysis seeks insights regarding these patients, especially noting the timing of sipuleucel-T relative to the other FDA-approved treatments in the modern era.METHODS:Men with mCRPC receiving sipuleucel-T, given every 2 weeks x 3, were eligible for PROCEED. Follow-up continued until death, study withdrawal, or a minimum of 3 years. Long-term survivors were defined as those who survived ≥3 yr. Baseline characteristics and treatments received pre/post-sipuleucel-T are reported in this ad-hoc subgroup analysis.RESULTS:From 2011-2014, 1902 men received ≥1 sipuleucel-T infusion. Of these, an estimated 42.3% survived ≥3yr. At baseline, long-term survivors (OS ≥3 yr) and those who survived <3 yr had no notable differences in laboratory measures or patterns of metastatic sprea...

Experience with sipuleucel-T in metastatic castration-resistant prostate cancer (mCRPC) with visceral spread from PROCEED.

174 Background: Trials of approved agents in mCRPC have reported shorter overall survival (OS) in men with visceral metastases (mets). The phase 3 IMPACT trial evaluated sipuleucel-T, an autologous cellular immunotherapy, in mCRPC but excluded visceral mets. PROCEED, a registry of mCRPC patients receiving sipuleucel-T, offers the first description of sipuleucel-T in patients with visceral mets. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T biweekly x 3. Dose adjustment for organ dysfunction was unnecessary. Men were followed until death, study withdrawal, or a minimum of 3 years. OS is reported in this post-hoc subgroup analysis. Results: 1902 men received ≥1 sipuleucel-T infusion between 2011-2014. Visceral mets (n = 90) included liver (n=21), lung (n=61), and brain (n=2) involvement. Compared to patients without visceral mets (Table), men with visceral mets had poorer performance status (PS) and higher baseline prostate-specific antigen (PSA). Median OS was 20.5 and 31.2 mo in those with and without visceral mets. Patients with liver and lung mets had a median OS of 16.3 and 21.0 mo, respectively. Activation of antigen-presenting cells, a measure of immune activation and product potency, was similar in those with and without visceral mets. Conclusions: Initial observations suggest that patients with mCRPC and visceral spread can activate their immune cells to produce sipuleucel-T, but have a shorter OS than those with bone and/or lymph node spread. (NCT01306890). Clinical trial information: NCT00065442. [Table: see text]

Real-world PROCEED registry data: Sipuleucel-T in elderly men with metastatic castration-resistant prostate cancer (mCRPC).

177 Background: Managing patients ≥ 80 years old (yo) with mCRPC is challenging, given the high prevalence of comorbidities, polypharmacy, organ dysfunction, and reduced performance status (PS). Balancing treatment benefit with safety and quality of life is particularly germane for this group. Sipuleucel-T, an autologous cellular immunotherapy for mCRPC, is generally well-tolerated. Prior analyses from PROCEED, a large registry for sipuleucel-T in men with mCRPC, demonstrated that upregulation of immune cells in these elderly patients is similar to that of younger men. Here, we report on this clinical experience. Methods: PROCEED enrolled men with mCRPC treated with sipuleucel-T given every 2 weeks x 3, with no dose adjustment for organ dysfunction or drug interactions. The elderly cohort included those ≥ 80 yo. Men were followed until death, study withdrawal, or a minimum of 3 years. Results: Of 1902 patients who received ≥1 sipuleucel-T infusion, 374 (19.7%) were ≥ 80 yo. Compared to men &lt; 80 yo (Table), this cohort was 14 years older, had worse Eastern Cooperative Oncology Group (ECOG) PS and higher prostate-specific antigen (PSA) at baseline. All grade (16.3% elderly v. 13.7% younger) and grade 3-5 (10.7% elderly v. 9.9% younger) serious adverse events were comparable between groups. However, the median overall survival (OS) of elderly men was 10.7 mo shorter than that of younger men (&lt; 80 yo). Conclusions: Sipuleucel-T was generally well-tolerated in those ≥ 80 yo in a real-world setting and may be considered a first-line option for the elderly with asymptomatic or minimally symptomatic mCRPC. As expected, OS was shorter than in younger patients. Clinical trial information: NCT01306890. [Table: see text]

MP29-19 SIPULEUCEL-T IMMUNOTHERAPY FOR CASTRATE-RESISTANT PROSTATE CANCER MODULATES SOLUBLE B7-H3: A NOVEL MECHANISM OF ACTION

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I1 Apr 2018MP29-19 SIPULEUCEL-T IMMUNOTHERAPY FOR CASTRATE-RESISTANT PROSTATE CANCER MODULATES SOLUBLE B7-H3: A NOVEL MECHANISM OF ACTION Andrew Chang, Smita Nair, Daniel George, and Brant Inman Andrew ChangAndrew Chang More articles by this author , Smita NairSmita Nair More articles by this author , Daniel GeorgeDaniel George More articles by this author , and Brant InmanBrant Inman More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.939AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES B7-H3 is an immune checkpoint molecule widely expressed by prostate cancer, that exists in soluble form in the blood, and that impairs T cell function. We examined whether a cell-based immunotherapy for castrate-resistant prostate cancer (CRPC), sipuleucel-T, might modulate B7-H3 as part of its mechanism of action. METHODS We conducted a clinical trial (NCT02036918) where men with lymph node predominant oligometastatic CRPC were randomized to undergo either (a) sipuleucel-T immunotherapy followed by salvage lymphadenectomy (n=15) or (b) salvage lymphadenectomy followed by sipuleucel-T (n=5). Serum samples were taken at baseline, prior to each sipuleucel-T leukapheresis session (x3), and two weeks after the last sipuleucel-T infusion. Serum samples were then tested in triplicate for soluble B7-H3 using a solid phase sandwich ELISA assay. The assay was calibrated against highly purified NS0-expressed recombinant human B7-H3. ELISA was performed in 90 well microplates that were read in a SpectraMax microplate reader at 450 nm with wavelength correction set to 540 nm. B7-H3 concentrations were calculated using a 4-parameter logistic model curve fit (Hill equation). Pre- and post-intervention serum B7-H3 levels were compared with a paired T test. RESULTS The mean minimum detectable dose of B7-H3 for the assay was 0.160 ng/mL. Vaccination with sipuleucel-T resulted in significant drop in serum B7-H3 levels from a mean pre-sipuleucel-T level of 29.6 ng/mL [SD = 6.7] to a mean post-sipuleucel-T level of 24.0 ng/mL [SD = 5.5] (P <0.001). In contradistinction, pre-surgery mean serum B7-H3 was 22.1 ng/mL (SD = 5.5) and post-surgery mean serum B7-H3 was 29.2 ng/mL (SD = 9.3), a difference of 7.1 ng/mL (P = 0.002), indicating that surgery caused an increase in serum B7-H3 levels (Figure). CONCLUSIONS Sipuleucel-T immunotherapy is known to prolong survival in CRPC. Our results suggest that one potential mechanism of action of this vaccine (and possibly other prostate cancer vaccines) is to reduce the production of soluble B7-H3 by prostate cancer cells, which could lead to improved immune responsiveness of the host immune system. However, the postoperative inflammatory response may abrogate some of this benefit. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e373 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Andrew Chang More articles by this author Smita Nair More articles by this author Daniel George More articles by this author Brant Inman More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

774P - Stride, a Randomized, Phase 2, Open-Label Study of Sipuleucel-T with Concurrent Vs Sequential Enzalutamide in Metastatic Castration-Resistant Prostate Cancer (Mcrpc)

ABSTRACT Aim: Multiple treatment options exist for patients (pts) with mCRPC, particularly in the setting of early metastasis. Sipuleucel-T, an autologous cellular immunotherapy, and enzalutamide, an androgen receptor inhibitor, are approved in the US and EU for treatment of mCRPC, but data are limited regarding use of these agents in combination. P12-2 (STRIDE; NCT01981122) is an ongoing, randomized, open-label, phase 2 study designed to evaluate concurrent vs sequential administration of sipuleucel-T and enzalutamide. Methods: Pts with asymptomatic or minimally symptomatic mCRPC are randomized 1:1 to receive sipuleucel-T with enzalutamide (160 mg QD for 52 wk) starting 2 wk before (concurrent arm [A]) or 10 wk after (sequential arm [B]) initiation of sipuleucel-T (3 infusions at 2-wk intervals). The primary endpoint is peripheral T cell immune response to PA2024, the immunizing antigen for sipuleucel-T. A secondary endpoint is time to recurrence of elevated serum PSA level. Results: As of April 7, 2014, 30 enrolled pts had completed sipuleucel-T infusions. At baseline, demographic and disease characteristics in arm A (n = 12) and arm B (n = 18) were generally comparable. Sipuleucel-T product parameters (antigen presenting cell [APC] activation, APC count, and total nucleated cell [TNC] count) did not differ significantly between the arms. A prime-boost effect on APCs was evident in both arms, as indicated by greater APC activation at infusions 2 and 3 than at infusion 1. The nature and incidences of adverse events (AEs) appeared to be similar between the arms and consistent with those previously reported with sipuleucel-T and enzalutamide. Overall, AEs occurred in 6 (50%) pts in arm A and 11 (61%) pts in arm B. Within 1 day of sipuleucel-T infusion, AEs occurred in 3 (25%) pts in arm A and 4 (22%) pts in arm B. No treatment-related grade ≥3 AEs were reported. Conclusions: Preliminary data suggest that sipuleucel-T potency, prime-boost, and safety are similar with and without concurrent enzalutamide. Data describing sipuleucel-T-induced peripheral immune responses with concurrent vs sequential enzalutamide will be presented at the meeting. Disclosure: D.P. Petrylak: Consultant or Advisory Role - Dendreon Corporation, Astellas - Self, compensated Corporate-sponsored Research - Dendreon Corporation, Astellas - Self, compensated; D.I. Quinn: Consultant, Honoraria: Dendreon, Medivation, Astellas, Pfizer, Bayer, Aveo, Algeta, Novartis, Amgen, Prometheus, Fresenius, Genentech, Jannsen-Self, compensated Sponsored research: Millenium, Sanofi-Aventis–Self Expert testimony: Medivation, Teva-Self; R. Dreicer: Consultant or Advisory Role: Medivation, Janssen, Dendreon, Roche, Millenium, Sanofi Aventis-Self, compensated Corporate-sponsored research: BIND, Progenics, Roche-Self; E.S. Antonarakis: Consultant or Advisory Role: Dendreon Corporation-Self, compensated Corporate-sponsored Research: Dendreon Corporation-Self; N.D. Shore: Consultant or Advisory Role: Algeta, Astellas, Bayer, Dendreon,Pfizer, Millenium, Janssen, Medivation, Sanofi-Self, compensated; J. Corman: Corporate-sponsored research: Dendreon Corporation-self R. Concepcion: Consultant or Advisory Role: Dendreon, Algeta, Bayer, MDxHealth, Cardinal Health,Chan Soon-Shiong Institute for Advanced Health-Self, compensated Corporate-sponsored Research: Janssen, Dendreon, Medivation, BNIT-Self; C.M. Pieczonka: Stock Ownership: Algeta-Self Consultant or Advisory Role: Dendreon-Self, compensated Honoraria: Dendreon, Astellas-Self; A.C. Stubbs: Employment: Dendreon Corporation-Self, compensated Stock Ownership: Dendreon Corporation-Self; N. Sheikh: Employment: Dendreon Corporation-Self, compensated Stock Ownership: Dendreon Corporation-Self; T. Devries: Employment: Dendreon Corporation Stock Ownership: Dendreon Corporation; A.S. Sandler: Employment: Dendreon Corporation Stock Ownership: Dendreon Corporation; C.G. Drake: Consultant or Advisory Role: Bristol Myers Squibb, Dendreon, Janssen, Pfizer, Roche-Self, compensated Corporate-sponsored Research: Aduro, Bristol Myers Squibb, Janssen-Self.

Open-label, multicenter study of sipuleucel-T in men with metastatic castrate-resistant prostate cancer (mCRPC) previously treated with sipuleucel-T: Evaluation of antigen presenting cell (APC) activation and ELISPOT data.

5053^ Background: P10-1 (NCT01338012) is a study of sipuleucel-T, an autologous cellular immunotherapy, in men with mCRPC previously treated with sipuleucel-T in PROTECT (NCT00779402). This preliminary analysis of P10-1 evaluates APC activation (a measure of product potency) and immune responses in men retreated with sipuleucelET. Methods: Men who received ≥1 infusion of sipuleucel-T in PROTECT and progressed to mCRPC were retreated with 3 infusions of sipuleucel-T. APC activation was assessed by CD54 upregulation. T cell responses to prostatic acid phosphatase (PAP) and PA2024 (PAP-GM-CSF) antigens were assessed by IFN-γELISPOT assay. Results: As of October 23, 2012, 7 men were enrolled and received ≥1 infusion. Median time between the third PROTECT infusion and first P10-1 infusion was 9.2 (range: 7.8–10.0) years. APC activation was greater at the first P10-1 treatment vs the last PROTECT treatment (Table). PA2024 and PAP ELISPOT responses were present prior to retreatment, indicating long-term memory (Table 1); based on other studies of sipuleucel-T, ELISPOT responses are not generally present prior to the first treatment (Beer. Clin Cancer Res 2011; Sheikh. Cancer Immunol Immunother 2013). Conclusions: This is the first trial to report the feasibility of sipuleucel-T retreatment following treatment in an earlier stage of prostate cancer. These data indicate the presence of existing immunological memory to the immunizing antigen several years after initial treatment. In addition, retreatment with sipuleucel-T appeared to boost product potency compared with prior treatment. Clinical trial information: NCT01338012. [Table: see text]

A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC).

5047^ Background: Sipuleucel-T and AA + P are FDA-approved for asymptomatic/minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1st study to evaluate the combination of sipuleucel-T and AA + P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the 1st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA + P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54+ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p&gt;0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA + P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA + P. Clinical trial information: NCT01487863.

A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.

5016 Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P&lt;.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.

P10-1 open-label, multicenter study of sipuleucel-T in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) previously treated with sipuleucel-T: Evaluation of antigen-presenting cell (APC) activation.

147 Background: Sipuleucel-T is an autologous cellular immunotherapy that has demonstrated an improvement in survival among men with asymptomatic or minimally symptomatic mCRPC. P10-1 (NCT01338012) is an open-label, multicenter study of sipuleucel-T in men with mCRPC previously treated with sipuleucel-T in the androgen-dependent setting on the PROTECT trial (a prospective, randomized, controlled Phase III study of sipuleucel-T in men with prostate-specific antigen recurrence following radical prostatectomy; NCT00779402). This preliminary analysis of P10-1 evaluates the pattern of APC activation in pts re-treated with sipuleucel-T after progression to mCRPC. Methods: Eligible pts include those previously treated with at least one infusion of sipuleucel-T on PROTECT and who progressed to the mCRPC state. Pts receive up to three additional infusions of sipuleucel-T. APC activation is assessed by CD54 upregulation expressed as the ratio of the average number of CD54 molecules on post-culture vs. pre-culture cells. Results: As of September 14, 2012, 7 pts have been enrolled and have received an infusion of sipuleucel-T. The median interval between the last infusion in PROTECT and the first infusion in P10-1 was 8.6 years. The Table shows a higher fold change in CD54 expression in the first P10-1 treatment compared with the initial infusion in PROTECT. Conclusions: This is the first report of pts re-treated with sipuleucel-T after prior treatment in an earlier disease setting. These preliminary data are consistent with the presence of an immunological memory response to the immunizing antigen several years following initial treatment. Clinical trial information: NCT01338012. [Table: see text]

A randomized phase II, open-label study of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC).

114 Background: Sipuleucel-T and AA are both FDA approved for mCRPC. Given that androgen deprivation therapy is immunostimulatory, increased suppression of the androgen axis with AA could provide synergy in combination with sipuleucel-T; however, AA is given with prednisone (P), which may be immunosuppressive. In order to evaluate the impact of concurrent AA + P on product characteristics, a study of sipuleucel-T with concurrent or sequential AA + P was undertaken. Methods: Pts aged ≥18 yrs with asymptomatic or minimally symptomatic mCRPC, and ECOG PS 0/1 were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-week intervals) with up to 26 weeks of AA + P (AA 1000mg QD + P 5mg BID) starting 1 day after the first sipuleucel-T infusion (concurrent arm) or at week 10 (sequential arm). The primary endpoint was cumulative CD54 upregulation (measure of antigen presenting cell activation); secondary and tertiary endpoints included CD54+cell and total nucleated cell (TNC) counts (measures of product potency), safety and efficacy. Results: 29 pts have been enrolled. 16 pts in the concurrent arm (A) and 13 pts in the sequential arm (B) have completed sipuleucel-T treatment at the time of this interim analysis (7 Sept 2012). 27/29 pts received all 3 infusions of sipuleucel-T; 2 pts (both arm A) received only 1 infusion due to insufficient TNC count (n=1) and disease progression 8 days after randomization (n=1). No significant differences in median cumulative CD54 upregulation (31.6 vs 36.6) and CD54+ count (1.9 vs 2.1 x109) were observed between arms A and B, respectively. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similarly, the TNC profile over time was similar for both arms. The overall incidence of adverse events (AEs) was similar in arms A (81%) and B (77%). Common all-grade AEs included muscle spasms (31% vs 23%), oral paresthesia (19% vs 31%), chills (31% vs 8%) and cough (19% vs 15%). Conclusions: These data suggest that sipuleucel-T can be manufactured during treatment with AA + P with product potency and prime boost similar to that of sipuleucel-T alone. Clinical trial information: NCT01487863.

Randomized phase II trial evaluating the optimal sequencing of sipuleucel-T and androgen-deprivation therapy (ADT) in patients (pts) with biochemically recurrent prostate cancer (BRPC).

34 Background: ADT is a standard therapy for pts with BRPC after failure of primary therapy, and has known immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is FDA approved for minimally or asymptomatic metastatic castrate-resistant prostate cancer. Here we report interim data from a phase 2 trial evaluating the optimal sequencing of sipuleucel-T and ADT by examining immune response markers in pts with BRPC at high risk for metastases (i.e., PSA doubling time ≤12 mo). Methods: Men were equally randomized to Arm 1: sipuleucel-T followed by ADT (started 2 wk after the final sipuleucel-T infusion); or Arm 2: ADT followed by sipuleucel-T (started after 3 mo of ADT). In both arms pts received 3 infusions of sipuleucel-T and 12 mo of ADT (2 × 45 mg leuprolide injections at 6 mo intervals). The primary endpoint was antigen-specific immune responses (ELISPOT to PA2024 [PAP-GM-CSF]). Secondary endpoints included safety and product parameters (CD54 upregulation, CD54+ and total nucleated cell counts). Results: 68 pts were randomized over 9 mo. Baseline characteristics were balanced across arms. Product parameters, evaluated in 31 and 17 pts in Arms 1 and 2, respectively, were similar between arms at the time of this analysis (26 Sept 2012). Antigen presenting cell activation patterns indicated a prime-boost effect (increased CD54 upregulation at infusions 2 and 3). Analysis of serum samples suggested that there were no differences between the arms in cellular (n=20; n=10) or humoral (n=22; n=13) immune responses to PA2024 or PAP (p&gt;0.05). Similar anti-tetanus titers were seen in both arms, indicating equivalent immunocompetence. To date, the combination of sipuleucel-T and ADT appears to be well tolerated with only 1 serious adverse event seen (vertigo, Arm 2). Conclusions: Preliminary data suggest that in men with BRPC, sipuleucel-T results in a similar prime-boost pattern of immune activation, and antigen-specific cellular and humoral responses, independent of ADT. Sipuleucel-T plus ADT appears to be well tolerated in these pts. Updated results will be presented. Clinical trial information: NCT01431391.

Real-world experience with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel (D): Data from PROCEED.

30^ Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for asymptomatic or minimally symptomatic mCRPC. The phase III IMPACT trial showed a significant improvement in overall survival with sipuleucel-T treatment (tmt). In IMPACT, D use was prohibited within 3 months prior to registration due to the potential immunosuppressive impact of chemotherapy. PROCEED is an ongoing, multicenter, phase 4 registry enrolling pts receiving sipuleucel-T in the real-world setting. Enrollment has no restrictions on D use; thus, data from PROCEED may help determine whether prior D affects sipuleucel-T manufacture. Here we present preliminary results on baseline demographics and product parameters in PROCEED subjects with and without prior D exposure. Methods: Pts who were treated with sipuleucel-T within the prior 6-months at clinical sites were asked to provide informed consent to participate in PROCEED. Results: By September 2012, 560 pts completed sipuleucel-T tmt; 15% previously received D (median 291 days prior to 1st sipuleucel-T infusion). Patients with prior D had higher PSA levels, and those with recent D use tended to have a lower performance status and higher Gleason scores, but product parameters were generally comparable between the groups (see table). Conclusions: Pts enrolled in PROCEED with and without prior D exposure had different baseline demographics and disease characteristics. However, sipuleucel-T product parameters were comparable regardless of prior D exposure. Clinical trial information: NCT01306890. [Table: see text]

Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.

2563 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). NeoACT (Study P07-1) was undertaken to investigate neoadjuvant sipuleucel-T treatment in subjects with localized prostate cancer. Methods: In this open-label, phase 2 study (NCT00715104), subjects with localized prostate cancer received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy (RP). Following RP, subjects were randomized 1:1 to receive / not receive a sipuleucel-T booster infusion 12 weeks post-RP. Cellular composition, antigen presenting cell (APC) activation, cytokines, and T and B cell activation were profiled before and after each culture with PA2024, the fusion protein containing prostatic acid phosphatase used to generate sipuleucel-T. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T, and 15 subjects received a booster infusion. Consistent with sipuleucel-T in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first (p&lt;0.001). The expression of early T cell activation markers (CD134, CD137, CD278 and CD279) were increased in pre-culture cells obtained after the first infusion, and further increased after culture. Activated mature B cells (CD20+CD27+IgD+CD86+) increased following culture in all 3 products (p&lt;0.01); memory B cells (CD20+CD27+IgD-CD86+) were progressively increased following the first infusion (p&lt;0.05 third vs. first product). TNF-α, IFN-γ, IL-2 were secreted at higher levels during culture of the second and third products (all p&lt;0.001). The observed increases in CD54 upregulation, early T cell activation markers, and memory and activated mature B cells were maintained at booster treatment. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that was consistent with boosting of an immune response primed with the first infusion. Immune activation was maintained at the booster infusion 3 months following initial sipuleucel-T treatment.

Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment.

2564 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32 patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (&gt;10% of patients) were fatigue, headache, and myalgia. Significant increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-Keuls test: p&lt;0.0001 for each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response.

Evaluation of immune activation following neoadjuvant sipuleucel-T in subjects with localized prostate cancer.

178 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). Methods: Subjects with localized prostate cancer were enrolled in an open-label, Phase 2 study (P07-1; NCT00715104 ) in which they received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to radical prostatectomy. All samples were evaluated for cellular composition and antigen presenting cell (APC) activation pre- and post-culture with PA2024, a fusion protein comprising prostatic acid phosphatase and granulocyte macrophage-colony stimulating factor. Additionally, cytokines within the culture supernatant were assessed, and T and B cell activation were evaluated pre- and post-culture using flow cytometry. Results: Of the 42 enrolled subjects (median age: 61 years; 98% Caucasian), 38 received all 3 infusions of sipuleucel-T. Consistent with previous trials in mCRPC, CD54 upregulation (APC activation) was greater at the second and third infusions relative to the first. While the percent of CD4+ and CD8+ T cells was unchanged with treatment, the expression of early T cell activation markers (CD134, CD137, CD278 and CD279) was increased in pre-culture cells obtained after the first infusion, and further increased post-culture. Similarly, while the percent of B cells was unchanged, there was a progressive increase in memory B cells (CD20+CD27+IgD−CD86+; pre- and post-culture) and activated mature B cells (CD20+CD27+IgD+CD86+; post-culture) following the first infusion. Activated T cell-associated cytokines were significantly elevated (TNF-α, P &lt; 0.001; IFN-γ, P &lt; 0.001; and IL-2, P &lt; 0.001) in the second and third products. Conclusions: Neoadjuvant sipuleucel-T resulted in robust immune system activation that included APCs, memory and activated mature B cells, and both CD4+ and CD8+ T cells. The patterns observed at the second and third infusions, relative to the first, are consistent with an immunological prime-boost profile.