Supplementary Table S1. Baseline demographics and disease characteristics in patients with mCRPC from the phase III sipuleucel-T trials included in the eosinophil analysis and the overall pooled population. Supplementary Figure S1. Overview of the study designs of three phase III clinical trials from which data were pooled for this retrospective analysis. Supplementary Figure S2. Changes in eosinophil counts for sipuleucel-T-treated patients with or without an elevated eosinophil count in randomized phase III trials, versus the control group. Supplementary Figure S3. Association of immune response with change in eosinophil counts for sipuleucel-T-treated patients in randomized phase III trials.

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

8032 Background: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%–45% vs 75%–80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV, ADCETRIS®), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy. Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n = 26); Part B: BV+dacarbazine (DTIC; 375 mg/m2; n = 19); Part C: BV+bendamustine (benda; 70 mg/m2; n = 20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n = 20). The efficacy evaluable (EE) set includes all patients who had at least 1 post-baseline response assessment (n = 25, 19, 17, 19). Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%–70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2019 data cutoff). ORR were high (92%, 100%, 100%, 95%) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median OS in the FAS set was 77.5 mo with monotherapy; 64.0, 46.9, and not reached in the combination parts. Treatment-related AE ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related SAEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%). Conclusions: Older patients with cHL and multiple comorbidities have very high response rates with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yr with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study. Clinical trial information: NCT01716806 .

Background In the ECHELON-2 phase 3 clinical trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed clinically meaningful and statistically significant efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by IHC. In addition to the ECHELON-2 study, response data are available from an additional 344 subjects with CD30-expressing PTCL and other large-cell lymphomas (including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma-NOS) who had been treated in studies with brentuximab vedotin as a single agent or in combination with chemotherapy, in both frontline and relapsed/refractory settings. Among these 344 subjects, 184 had tumors with CD30 expression &lt;10% by local assessment, including 83/184 with undetectable CD30 by immunohistochemistry (CD30=0). Responses to brentuximab vedotin have been observed at all levels of CD30 expression, including in tumors with undetectable CD30 levels (Advani 2019; Horwitz 2019). It is hypothesized that A+CHP will demonstrate efficacy in subjects with PTCL and CD30 expression &lt;10% because: i) brentuximab vedotin has shown activity in lymphomas with low CD30 expression; and ii) the activity of CHP chemotherapy in PTCL is unrelated to CD30 expression. This study will include subjects with PTCL subtypes other than systemic anaplastic large cell lymphoma (sALCL). Study Design and Methods This is a dual-cohort, open-label, multicenter, phase 2 clinical trial designed to evaluate the efficacy and safety of A+CHP in subjects with non-sALCL PTCL and CD30 expression &lt;10% on tumor cells. Enrollment will be based on CD30 expression per local lab assessment. Subjects will be assigned to 1 of 2 cohorts based on CD30 expression; up to approximately 40 subjects will be enrolled in the CD30 negative (expression &lt;1%) cohort and approximately 40 subjects will be enrolled in the CD30 positive (expression ≥1% to &lt;10%) cohort. An archived tumor biopsy specimen will be submitted to a central pathology lab for confirmation of CD30 expression. Only subjects with CD30 expression &lt;10% per central confirmation will be analyzed for the primary and secondary endpoints. Subjects will receive 21-day cycles of A+CHP for a target of 6-8 cycles. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR). Key secondary endpoints include CR and PFS per BICR and overall survival. Key inclusion criteria include the following: subjects aged 18 years and older with newly diagnosed PTCL, excluding sALCL, per the WHO 2016 classification; CD30 expression &lt;10% by local assessment; and fluorodeoxyglucose-avid disease by PET and measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Lymphoma response and progression will be assessed by BICR using Revised Response Criteria for Malignant Lymphoma and modified Lugano criteria. A CT scan will be performed at the time of suspected clinical progression. Subsequent restage assessments (CT scans only) will be performed according to the calendar, relative to the first dose of study treatment, to ensure that tumor progression is uniformly assessed between the treatment arms. Efficacy and safety endpoints will be summarized with descriptive statistics by cohort, with the CD30 negative cohort and the CD30 positive cohort. The summary of overall (CD30 negative and positive cohort combined) may be presented as appropriate. Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be used to describe continuous variables. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier methodology and Kaplan-Meier plots will be presented. Medians for time-to-event analyses (eg, median PFS), will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. The trial will have sites open in the US and multiple countries in Europe, with enrollment planning to begin in September 2020. Disclosures Jagadeesh: Verastem: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Debiopharm Group: Research Funding; Regeneron: Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Horwitz:ASTEX: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Portola: Consultancy, Research Funding.

TPS8069 Background: Older patients and those with significant comorbidities have not attained outcomes seen in younger patients with classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL). Five-year progression-free survival (PFS) was 30%–45% in older HL patients treated with combination chemotherapy versus 75%–80% in younger patients (Evens 2008; Proctor 2009). Similarly, when adjusted for age, a Charleston Comorbidity Index ≥2 was independently associated with worse overall survival (HR=1.63) and PFS (HR=1.54) (Ellin 2018). Brentuximab vedotin (BV, ADCETRIS), a CD30-directed antibody-drug conjugate, has robust activity in cHL patients refractory to several lines of chemotherapy. BV monotherapy in 27 cHL patients aged ≥60 years had a 92% objective response rate (ORR) and 73% achieved complete remission (Forero-Torres, 2015). BV was also active and well-tolerated in CD30-expressing PTCL patients with relapsed or refractory disease (Horwitz 2014). Frontline BV monotherapy may have the potential to be an active and well-tolerated treatment for cHL and PTCL patients who are older or have significant comorbidities, which are populations with high unmet need. Methods: This phase II, open-label study, SGN35-015 (NCT01716806), has added 2 cohorts to evaluate the efficacy and tolerability of BV monotherapy in treatment naive patients with cHL, (Part E), or CD30-expressing PTCL (Part F, n~50 each) who are unsuitable for conventional combination therapy due to comorbidity-related factors as determined by a Cumulative Illness Rating Scale (CIRS) score ≥10 or dependence on others for any instrumental activities of daily living. Eligible patients must also have an Eastern Cooperative Oncology Group (ECOG) performance status ≤3 and measurable disease ≥1.5 cm per radiographic techniques. BV (1.8 mg/kg) will be administered as a single intravenous infusion on day 1 of each 2-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Response will be assessed by blinded independent central review of spiral CT and PET scans at Cycles 2, 6, 11, and at end of treatment to be graded per Lugano 2014. The primary objective of these cohorts is to assess ORR of frontline therapy with single-agent BV in patients who have significant comorbidities. Clinical trial information: NCT01716806 .

There is an increased focus on improving outcomes of prostate cancer (PC) patients (pts) by introducing treatments before castration resistance occurs. Results from CHAARTED (Sweeney NEJM. 2015) and STAMPEDE (James Lancet. 2015) demonstrate a survival advantage with ADT (gonadotropin-releasing hormone analog or surgical castration) in combination with docetaxel (DOC) for pts with metastatic PC, and practice guidelines recommend ADT + DOC for pts with metastatic disease. Inhibition of the androgen receptor (AR) in addition to ADT may provide more complete blockade of androgen signaling vs ADT alone. We hypothesize that apalutamide (APA), a selective AR antagonist, plus ADT will improve radiographic progression-free survival (rPFS) and overall survival (OS) compared with ADT alone, and have an acceptable safety profile in pts with mHSPC. Trial design: This is a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of APA + ADT in pts with Eastern Cooperative Oncology Group performance status ≤ 1 and mHSPC (metastatic disease documented by ≥ 1 bone lesions with or without visceral metastasis). Pts will be stratified by Gleason score (≤ 7 vs > 7), region (North America, European Union vs other), and prior DOC use (yes/no). Up to 6 cycles of DOC for mHSPC is allowed, with last dose within 2 mos of randomization. Up to 6 mos ADT for mHSPC is allowed prior to randomization. Approximately 1000 pts will be randomized (1:1) to APA (240 mg/d) + ADT or placebo + ADT in 28-day cycles. Co-primary end points: rPFS and OS. Secondary end points: time to pain progression, time to skeletal-related event, time to chronic opioid use, and time to initiation of cytotoxic chemotherapy. Samples for pharmacokinetics and biomarkers will be collected to correlate with clinical parameters. An independent data monitoring committee will review safety and efficacy data. Clinical trial identification: NCT02489318 Legal entity responsible for the study: Janssen Global Services, LLC Janssen Global Services, LLC

AbstractSipuleucel-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. Cancer Immunol Res; 2(10); 988–99. ©2014 AACR.

296^ Background: DN24-02 is an investigational autologous cellular immunotherapy (ACI) consisting of antigen presenting cells (APCs) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to granulocyte-macrophage colony-stimulating factor. In the ongoing NeuACT (N10-1; NCT01353222) trial, patients (pts) with high-risk, HER2+ urothelial cancer (UC) are randomized 1:1 to either adjuvant DN24-02 or surveillance. Updated analyses are presented. Methods: Eligibility criteria include radical surgical resection of primary ≥pT2 or pN+ UC (bladder or upper tract) with HER2 expression ≥1+ by immunohistochemistry. Pts randomized to DN24-02 undergo 3 cycles of leukapheresis and infusion at 2-week intervals. Product potency is assessed at each infusion. Immune responses and adverse events (AEs) are measured at multiple time points. Results: By July 2013, tumor specimens from 226 pts had been screened. Of these, 75% (95% CI 69–81%) had HER2 expression of ≥1+ in the primary tumor, 32% had ≥2+ and 8% had 3+. In pts with available lymph node samples (n=83), 84% (95% CI 75–91%) had a HER2 score of ≥1+ in the lymph nodes; 49% and 14% had ≥2+ and 3+, respectively. Pts with 1+ HER2 expression had similar immune responses to BA7072 as those with higher HER2 levels. APC activation (CD54 upregulation) was observed at each infusion in the first 30 pts who had completed the 3 infusions, but was typically greater at infusions 2 (median 15.56; range: 6.42–23.97) and 3 (14.69; 8.24–30.86) than infusion 1 (7.35; 4.04–14.34). In the 5 pts with available data, BA7072 and HER500 specific antibody responses increased from baseline for at least 12 months. Most (92.3%) AEs were grade 1–2 in severity, including all AEs that occurred ≤1 day after infusion. Conclusions: The high frequencies (≥75%) of ≥1+ HER2 scores in primary tumor and lymph node samples confirm that HER2 expression is common in muscle-invasive and node+ UC. DN24-02 product potency data suggest an immunologic prime-boost effect. The observed humoral responses are the first data suggesting prolonged immune responses with an ACI in UC. Most AEs were grade 1–2 in severity. Clinical trial information: NCT01353222.

Immunotherapy encourages the recipient's own immune response to destroy cancer cells, and current evidence suggests that immunotherapies may be most beneficial in early metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first therapeutic cancer vaccine to be approved by both the US Food and Drug Administration and European Medicines Agency for the treatment of asymptomatic or minimally symptomatic mCRPC. Combining immunotherapy with other treatments may have potent anticancer effects; cytoreductive therapies can release tumor antigens and promote a proinflammatory environment that could augment immunotherapies. However, some cytoreductive agents or coadministered drugs may be immunosuppressive. Understanding these interactions between different mCRPC treatment modalities may offer further potential to improve patient outcomes.

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-gamma 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.

Radiotherapy has conventionally been viewed as immunosuppressive, which has precluded its use in combination with immunotherapy for prostate and other cancers. However, the relationship between ionizing radiation and immune reactivity is now known to be more complex than was previously thought, and data on the use of radiotherapy and immunotherapy are accumulating. Herein, we review this topic in the light of recently available data in the prostate cancer setting. Recent research has shown no significant lymphopenia in patients undergoing radiotherapy for high-risk adenocarcinoma of the prostate. In addition, emerging evidence suggests that radiotherapy can have immunostimulatory effects, and that tumor cell death, coupled with related changes in antigen availability and inflammatory signals, can affect lymphocyte and dendritic cell activation. Initial studies have focused on combinations of tumor irradiation and immunotherapy, such as the autologous cellular immunotherapy sipuleucel-T and the monoclonal antibody ipilimumab, in metastatic castration-resistant prostate cancer. These combinations appear to have clinical promise, and further investigation of the potentially synergistic combination of radiotherapy and immunotherapy is continuing in clinical trials.

TPS187 Background: Despite surgical resection and the use of neoadjuvant or adjuvant chemotherapy, up to 50% of patients with invasive urothelial carcinoma experience disease recurrence and eventually die of metastatic disease. New therapeutic approaches are needed for these patients. Approximately 50% of patients with pathologic high risk features have evidence of HER2 expression on the primary tumor or involved lymph nodes. DN24-02 is an autologous cellular immunotherapy targeting HER2, and is based on the same platform as sipuleucel-T, which was approved by FDA in 2010 for treatment of men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Each dose of DN24-02 is manufactured by culture of peripheral blood mononuclear cells (PBMCs) obtained by leukapheresis with the recombinant antigen BA7072, which comprises components of the intra- and extracellular domains of the HER2 antigen linked to GM-CSF. A product similar to DN24-02 has demonstrated evidence of safety and immune response in phase I studies. The primary objective is to determine whether DN24-02 given as adjuvant therapy following surgical resection can prolong survival compared to the control group. Secondary objectives are to evaluate disease-free survival, safety, and immune responses to DN24-02. Methods: Eligible patients will have undergone surgical resection of a primary urothelial cancer, with either ≥pT2 or pN+ staging, and HER2 expression ≥ 1+ by IHC based on pathologic review. Up to 180 subjects will be randomized (1:1) to receive DN24-02 as adjuvant therapy approximately every 2 weeks, given as IV infusions 3 times, or standard of care. Stratification will include 1) neoadjuvant chemotherapy vs. surgery alone; and 2) positive (pN+) vs. negative lymph node involvement (pN0). Adjuvant chemotherapy will not be allowed. Patients can be treated per standard of care if there is disease recurrence. Patients will be monitored for evidence of disease recurrence by imaging, and will be followed for survival. Cellular and serological immune responses will be assessed at baseline and post-DN24-02 therapy.

201 Background: Traditional wisdom has suggested that under some circumstances radiation therapy may be immunosuppressive, thus obviating effective combination approaches with immunotherapy. Our purpose was to test whether standard radiation therapy for high-risk prostate cancer are immune modulating, thereby prohibiting potential combination with cellular based immunotherapies such as sipuleucel-T. Methods: Retrospective analysis of complete blood count with differential (CBC) data was performed on 26 patients with high-risk adenocarcinoma of the prostate undergoing external beam radiation therapy between January 2008 and November 2010. CBC data were collected prior to radiation therapy and at up to 4 time points thereafter, and compared to normal ranges from an outside reference lab (WBC 3,800-10,700/μL; ALC 910-4,280/μL). Results: The median age was 73 (range 62-86), and 16 patients were on concurrent androgen deprivation therapy. Patients received intensity modulated, dose-escalated external beam radiotherapy. Baseline and subsequent median white blood counts (WBC) and absolute lymphocyte counts (ALC) remained within the normal ranges. In the clinically relevant time frame of <3 months following radiation therapy where sipuleucel-T could be considered, the WBC and ALC were 5,350 and 970, respectively. The median WBC and ALC then gradually increased to 5,800 and 1,250, respectively, at 6-12 months post radiation therapy. Conclusions: These data suggest that in the setting of external beam radiation approaches for high-risk adenocarcinoma of the prostate, no significant changes in either WBC or ALC were observed. The hematologic status in these patients remained stable, suggesting that combination radiation / cellular based immunotherapy approaches are feasible. Further analysis is warranted to test the potential of novel immunotherapeutic agents with radiation therapy. [Table: see text]

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]

You have accessJournal of UrologyProstate Cancer: Advanced (III)1 Apr 2013971 SAFETY AND CHANGES IN LABORATORY PARAMETERS ASSOCIATED WITH SIPULEUCEL-T IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER: PHASE 2 PROACT STUDY Thomas Gardner, Daniel Petrylak, John Corman, Simon Hall, Ralph Weinstein, Robert Sims, Todd DeVries, and Celestia Higano Thomas GardnerThomas Gardner Indianapolis, IN More articles by this author , Daniel PetrylakDaniel Petrylak New York, NY More articles by this author , John CormanJohn Corman Seattle, WA More articles by this author , Simon HallSimon Hall New York, NY More articles by this author , Ralph WeinsteinRalph Weinstein Portland, OR More articles by this author , Robert SimsRobert Sims Seattle, WA More articles by this author , Todd DeVriesTodd DeVries Seattle, WA More articles by this author , and Celestia HiganoCelestia Higano Seattle, WA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.552AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T prepared using the FDA-approved concentration of 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT (P07-2; NCT00715078) is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using three different concentrations (2, 5 or 10μg/mL) of PA2024. Here we report the preliminary safety analysis and changes in laboratory parameters. METHODS Patients (pts) with asymptomatic or minimally symptomatic mCRPC received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-week intervals. Adverse events (AEs) were recorded continuously and laboratory samples for assessment were taken 2, 4 and 6 months (mos) after the first infusion. RESULTS 120 pts were included in the safety analysis (2μg/mL, n=40; 5μg/mL, n=40; 10μg/mL, n=40). Baseline characteristics were balanced across the arms. The most common AEs (occurring in >20% of pts in the total population) were fatigue (44.2%), back pain (30.8%), nausea (30.8%), arthralgia (25.8%) and chills (25.8%), with a consistent incidence of these AEs across treatment arms. AEs occurring within 1 day of infusion (in >20% of pts in the total population) included fatigue (23.3%) and chills (20.8%). Treatment-related serious AEs occurred in 4 pts (3.3%), with fatigue (n=3) and dehydration (n=2) the only events occurring in more than 1 pt. Globulin protein levels increased significantly (p<0.05) from baseline at all time points in the 5μg/mL and 10μg/mL arms and at 2 mos in the 2μg/mL arm. Significant increases in eosinophil counts from baseline were observed at 2 mos in the 5μg/mL and 10μg/mL arms (p<0.05). There was no significant difference between treatment arms in immune responder frequencies (any immune response at any time point). CONCLUSIONS Increases in globulin protein and transient increases in eosinophil counts are consistent with previous studies, which showed that these changes in laboratory parameters positively correlate with immune response and OS, respectively, and thus may be surrogates for immune response. Furthermore, these data suggest that sipuleucel-T manufactured using 3 different concentrations of PA2024 has an acceptable safety profile. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e399 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Thomas Gardner Indianapolis, IN More articles by this author Daniel Petrylak New York, NY More articles by this author John Corman Seattle, WA More articles by this author Simon Hall New York, NY More articles by this author Ralph Weinstein Portland, OR More articles by this author Robert Sims Seattle, WA More articles by this author Todd DeVries Seattle, WA More articles by this author Celestia Higano Seattle, WA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

148 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using 3 different concentrations of PA2024. Here we report data from the FDA-approved concentration, 10μg/mL PA2024 (n=40). METHODS Pts with asymptomatic or minimally symptomatic mCRPC (n=120) received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-wk intervals. Peripheral immune responses were evaluated 2, 4 and 6 mo after 1st infusion by serum ELISA (n=40), and B cell activation phenotype was characterized during the manufacture of the product by flow cytometry (n=19). RESULTS During product manufacture both mature and memory B cells were activated; the percentage of B cells that had a mature phenotype (defined as CD20+ IgD+ CD27+ CD86+) was increased only after culture of each successive treatment. Activated memory B cells (defined as CD20+ IgD- CD27+ CD86+) were also increased after culture of each successive treatment and in pre-culture cells at the 3rd treatment. At mo 2, median serum anti-PA2024 and anti-PAP titers (IgG and IgM combined) were 128 and 32-fold higher vs baseline respectively, compared to median serum anti-GM-CSF titers, which were 16-fold higher vs baseline. Median serum anti-PA2024 titers (IgG and IgM combined) were significantly higher than those for anti-GM-CSF (p<0.001) at all timepoints and correlated with anti-PAP titers (r=0.840). PA2024 and PAP responder frequencies (IgG and IgM titers combined >12,800) were 79% and 47% of pts, respectively. Anti-tetanus titers were predominantly IgG and did not differ between timepoints. CONCLUSIONS These data indicate that sipuleucel-T induces an activated memory phenotype, evident after each culture in vivo after the first two treatments. Sipuleucel-T also appears to generate robust, long lasting anti-PA2024 and anti-PAP responses. Analyses comparing the 3 dosing cohorts will be reported in future publications. CLINICAL TRIAL INFORMATION NCT00715078.

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]