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IntroductionThe treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to evolve. Sipuleucel-T was the first immunotherapy approved by the US Food and Drug Administration (FDA) to treat asymptomatic or minimally symptomatic mCRPC. The androgen receptor-targeting agents (ARTAs) abiraterone acetate and enzalutamide were initially approved to treat mCRPC. Looking at chemotherapy-naïve men with mCRPC, we compared survival outcomes between the sipuleucel-T + ARTA cohort (men who received either sipuleucel-T or an ARTA in the first line, and then the other in the second line within 6 months) and the ARTA monotherapy cohort (men who only received ARTA monotherapy).MethodsThis retrospective cohort analysis used longitudinal, adjudicated claims data from the US Medicare Fee-for-Service 100% research identifiable dataset that includes both urologic and oncologic practice settings. Eligible men started their first mCRPC treatment with either sipuleucel-T or ARTA in either 2014 or 2015 and had continuous Medicare Parts A, B, and D eligibility for the subsequent 3 years. A multivariable Cox proportional hazards regression model was used to analyze overall survival (OS), both overall and by index year, and to control for differences.ResultsThe sipuleucel-T + ARTA and ARTA monotherapy cohorts comprised 773 and 4642 men, respectively, with different characteristics at treatment start. The most commonly used ARTAs were enzalutamide in the former and abiraterone in the latter cohort. Median OS was 30.4 and 14.3 months in the sipuleucel-T + ARTA and ARTA monotherapy cohorts, respectively, with the sipuleucel-T + ARTA cohort having a 28.3% lower risk of death than the ARTA monotherapy cohort (hazard ratio 0.717; 95% CI 0.648, 0.793; p < 0.01).ConclusionsThis real-world study of mCRPC treatment indicates that men receiving sipuleucel-T and ARTAs had a longer median OS than patients receiving treatment with an ARTA alone, suggesting that leveraging mechanisms of action can be beneficial in treating patients with mCRPC.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02085-6.

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.

Abstract 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 2017). Herein we analyzed PROCEED (NCT01306890), a large real-world registry, in which all patients received sipuleucel-T. Previously presented at ASCO Annual Meeting 2019 (Sartor 2019).METHODS: In PROCEED, 1902 mCRPC patients received 1 or more sipuleucel-T infusions. 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&amp;lt;0.001). Sipuleucel-T-treated AAs with lower baseline PSA had markedly longer median OS vs sipuleucel-T-treated CAUs. Among those with PSA less than or equal to 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&amp;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&amp;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. REFERENCES: Sartor 2012 (DOI: 10.1200/JCO.2019.37.15_suppl.5035); McLeod 2012 (DOI: 10.1016/j.juro.2012.02.1051); Moses KA et al 2017 (DOI: 10.1016/j.urology.2016.07.045); Schellhammer 2013 (DOI: 10.1016/j.urology.2013.01.061) Citation Format: Oliver Sartor, Andrew J Armstrong, Chiledum Ahaghotu, David G McLeod, Matthew R Cooperberg, David F Penson, Philip W Kantoff, Nicholas J Vogelzang, Arif Hussain, Christopher. M Pieczonka, Neal D Shore, David I Quinn, Elisabeth I Heath, Ronald F Tutrone, Paul F Schellhammer, Matthew Harmon, Nancy N Chang, Stephen J Freedland, Celestia S Higano. 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 [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D084.

BackgroundAlthough radical cystectomy (RC) is a standard treatment for muscle-invasive bladder cancer (MIBC), for many patients the risks versus benefits of RC may favor other approaches. We sought to define the landscape of early postcystectomy mortality in the United States and identify patients at high risk using pretreatment variables.MethodsWe identified patients with MIBC (cT2-T4aN0M0) who underwent RC without perioperative chemotherapy within the National Cancer Database (2003–2012). Using multistate multivariable modeling, we calculated time spent in three health states: hospitalized, discharged, and death more than 90 days postcystectomy. Cross-validation was performed by geographic region. Time spent in each state was weighted by utility to determine 90-day quality-adjusted life days (QALDs).ResultsAmong 7922 patients, 90-day mortality was 7.6% (8.0% for lower and 6.7% for higher volume hospitals). Increasing age, clinical T stage, Charlson Comorbidity Index, and lower volume were associated with higher 90-day mortality and were included in the model. Cross-validation revealed appropriate performance (C-statistics of 0.53–0.74; calibration slopes of 0.50–1.67). The model predicted 25% of patients had a 90-day mortality risk higher than 10%, and observed 90-day mortality in this group was 14.0% (95% CI = 12.5% to 15.6%). Mean quality-adjusted life days (QALDs) was 63 (range = 44–68).ConclusionsRC is associated with relatively high early mortality risk. Pretreatment variables may identify patients at particularly high risk, which may inform clinical trial design, facilitate shared decision making, and enhance quality improvement initiatives.

e17018Background: Sip-T is a cellular immunotherapy approved for treatment of asymptomatic/minimally symptomatic mCRPC on the basis of improved OS. Across 4 clinical trials, CVEs occurred in 3.5% o...

5072Background: Sip-T, an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), induces antibody responses to prostati...

309 Background: Sip-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T’s induction of B-cell responses to PAP and other antigens correlates with improved survival (Sheikh 2013, GuhaThakurta 2015). Cancer vaccine-induced changes to BCR repertoire are unknown. To assess changes in BCR repertoire upon booster treatment, we compared patients retreated with sip-T (P10-1) to treatment-naïve patients (STRIDE). Methods: STRIDE pts (N = 52) received sip-T with concurrent or sequential enzalutamide for mCRPC (Petrylak 2015). P10-1 pts (N = 8) previously treated with sip-T for androgen-dependent PC were retreated with a booster course for mCRPC, after a median of 8.9 years (Beer 2017). Blood samples were collected at baseline (wk 0) and during (wk 2, 4)/post-sip-T (wk 6, 26, 52). Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). BCR diversity was assessed by clonality, and BCR dynamics by fold-change analysis (Zhang 2017). Results: BCR repertoire had significantly higher clonality in P10-1 vs STRIDE (wk 0: p = 0.003, wk 2: p &lt; 0.001, wk 4: p &lt; 0.001), suggestive of a more focused BCR repertoire. P10-1 also showed increased clonality from wk 0 to 4 (p = 0.063), whereas STRIDE showed a significant increase in clonality from wk 0 to 6 (p = 0.039), suggesting that BCR repertoire focused earlier in P10-1. Starting at wk 2, more clones remained in the repertoire in P10-1, indicating that sip-T stimulated immunologic memory early, after 1st retreatment (p &lt; 0.05). There was less change over time (clonal shuffling) within the 100 most abundant baseline clones in P10-1 (p = 0.080), suggesting more relevant clones preexisted at baseline and enriched over time. After the first two sip-T infusions, more clones contracted in P10-1 (p = 0.027, p = 0.014), whereas more new clones were generated in STRIDE (p = 0.083, p = 0.003). Conclusions: Sip-T induces long-lasting changes in the BCR repertoire. Sip-T retreatment leads to quicker focusing of BCR repertoire than initial treatment. These results are consistent with sip-T inducing durable immunologic memory.

Abstract Immunotherapy has demonstrated significant clinical benefit in different cancers. T cells are a crucial component of the adaptive immune system and mediate anti-tumoral immunity. Antigen-specific recognition by T cells is via T cell receptor (TCR) which is the product of somatic V(D)J gene recombination with the addition/subtraction of nontemplated bases at recombination junctions. Next generation TCR sequencing effectively profiles the TCR repertoire. Currently TCR analyses quantify diversity across single clones, however, due to the low overlap of clones across samples, such analyses are limited to a single sample. Here we extend our previous analysis pipeline to track and examine TCR repertoire across time by focusing on V and J gene segments, overcoming the limitation of contemporary analytical approaches and thus obtain statistical inference across subjects directly. The published data of TCR profiling of serial peripheral blood mononuclear cells (PBMC) from three healthy subjects and five prostate cancer patients enrolled in an open-label, Phase II clinical trial of neoadjuvant sipuleucel-T (sip-T) were used as the basis of this analyses. After consolidating the clonal abundance for each combination of V and J gene segments, we calculated Pielou’s evenness, which demonstrates that sip-T treated subjects displayed greater clonal expansion compared to healthy subjects (P&amp;lt;0.001). The Circos table viewer was used to circularly visualize the distribution of the combination of V and J gene segments. Sip-T treated subjects were successfully distinguished from healthy subjects with 12 V and J gene combinations explaining the majority of variance of the patients by applying principle components analysis (PCA). Furthermore, we developed a customized clustering workflow to cluster the combination of V and J gene segments based on the change in abundance over time, with gap statistics employed to estimate the optimal number of clusters and k-means algorithm used for partitioning. We found that for all the prostate cancer patients assessed, TCRBV06/TCRBJ01, TCRBV05/TCRBJ02 and TCRBV06/TCRBJ02, which were in the same cluster with the highest frequencies, expanded after first treatment and were maintained at high frequencies at later time points. The results demonstrate that in the setting of immune modulation after sip-T treatment, the V(D)J recombination is not entirely random, and that this non-randomness can be used to distinguish T cell repertoires from sip-T treated subjects versus healthy subjects. The use of additional information of V and J gene segments enables to investigate the profiling of TCR repertoire from a different angle and add another layer of understanding of TCR repertoire. The application of PCA and the customized clustering complete our initial workflow for TCR sequencing data. Citation Format: Li Zhang, Sounak Chakraborty, Jason Cham, David Oh, Nadeem Sheikh, Lawrence Fong. Clustering analysis of next-generation sequencing T cell repertoire data in sipuleucel-T treated prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 549. doi:10.1158/1538-7445.AM2017-549

162 Background: Sip-T is an FDA-approved immunotherapy for patients (pts) with asymptomatic or minimally symptomatic metastatic CRPC. Sip-T is manufactured from autologous peripheral blood mononuclear cells cultured with the immunogen PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony-stimulating factor. After sip-T, antibody and T cell responses to PA2024 and/or PAP correlate with improved survival. To further elucidate the mechanism of sip-T–induced immune responses, we evaluated the proliferative and lytic ability of PA2024- and PAP-specific CD8+ T cells. Methods: Mononuclear blood cells were labeled with the membrane dye carboxyfluorescein succinimidyl ester (CFSE) and cultured with PA2024 or PAP. In vitro proliferative and lytic CD8+ (cytotoxic T lymphocyte [CTL]) T cell responses to these antigens were evaluated by flow cytometry. For proliferation, progressive dilution of CFSE was measured. For CTL activity, the loss of intracellular granzyme B (GzB), indicating exocytosis of this apoptosis-mediating enzyme, was assessed. Samples were from 2 sip-T clinical trials STAND (NCT01431391) and STRIDE (NCT01981122), hormone-sensitive and CRPC pts, respectively. Results: Six wk after sip-T administration, CD8+ PAP- and PA2024-specific responses were observed (n=14 pts assessed). The magnitude of PA2024-specific CD8+ proliferative responses was greater than that for PAP-specific responses. CD8+ T cells from a subset of pts who exhibited PA2024- and/or PAP-specific proliferative responses were assessed for lytic ability. After in vitro antigen stimulation, CTL activity in all evaluated samples (n=14, PA2024; n=13, PAP) was demonstrated by a significant decrease (p&lt;0.05) in intracellular GzB relative to a no-antigen control. Conclusions: Sip-T induced CD8+ CTL proliferation against the target antigens PAP and PA2024. Moreover, antigen-specific CTL activity provides the first direct evidence that sip-T can induce tumor cell lysis. These antigen-specific CD8+ lytic abilities were observed within 6 wk following sip-T, suggesting rapidly generated immune responses. Clinical trial information: NCT01431391; NCT01981122.