bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostate cancer associated natural killer cells show a pro-angiogenic and pro-inflammatory phenotype.
Authors: Albini Adriana , Bruno Antonino , Gallazzi Matteo , Naselli Angelo , Mortara Lorenzo , Noonan Douglas M 
Published: May 2020

e17544 Background: Prostate cancer (PCa) represents the second most common cancer worldwide in men. Angiogenesis has been shown to play a crucial role in PCa progression in several preclinical models. Production of pro-angiogenic factors can correlate with metastasis, Gleason score and prognosis in PCa and plasma levels of VEGF were shown to be higher in patients with metastatic PCa than those with localized disease. Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been found to be immunosuppressed in solid cancers, including PCa. Methods: Here, we phenotypically and functionally characterize circulating NK cells from PCa patients and their interaction with endothelial cells and macrophages. NK cell subset distribution has been investigated by multicolor flow cytometry (FACS) for surface antigens on peripheral blood samples PCa patients (TANKs). Conditioned media (CM) from FACS-sorted TANKs were used for functional studies of angiogenesis, on human umbilical-vein endothelial cells (HUVEC), studies for macrophage recruitment (migration assay on Boyden chambers) and polarization. Molecular studies were performed by real time PCR (qPCR) on HUCECs and macrophages exposed to CM of TANKs. Protein arrays were performed to characterize the secretome on FACS-sorted TANKs. Results: We found that TANKs acquire a pro-angiogenic/ dNK-like CD56brightCD9+CD49a+CXCR4+ phenotype. The same phenotype was observed on cytolytic NK cells, from healthy donors, exposed to CMs of three different PCa cell lines (PC-3, DU-145, LNCaP), together with increased production of CXCL8, Angiogenin, Angiopoietin1 and reduced production of TNFa, IFNg and GranzymeA. CMs from TANKs support the formation on capillary-like structures on HUVEC, together with increased expression of VEGF, VEGR-2, CXCL8, ICAM-1 and VCAM-1. Secretome analysis revealed the ability of TANKs release pro-angiogenic pro-invasive factors (CLXL8, MMP-1, MMP-9; uPAR) and cytokines/chemokines involved in macrophage recruitment (CCL1, CCL2, CCL5, CCL7, CCL13, CXCL1, CXCL11) and M2-like polarization (IL-10). Finally, CMs from TANKs can recruit THP-1 monocyte and polarize THP-1 macrophage towards CD206, Arginase1, CXCL8-expressing M2-like/TAM phenotype. Conclusions: Our results place PCa TANKs as effector cells able in supporting angiogenesis in PCa by directly interaction with endothelial cells and via macrophage polarization.
Circulating tumor DNA-targeted sequencing to reveal germline and somatic alterations that can guide decision-making in metastatic castration-resistant prostate cancer.
Authors: Dong Baijun , Fan Liancheng , Yang Bin , Chen Wei , Li Yonghong , Wu Kaijie , Zhang Fengbo , Dong Haiying , Cheng Huihua , Yang Yining , Li Lei , Yao Xudong , Xue Wei 
Published: May 2020

e17556 Background: The genomic landscape of metastatic castration-resistant prostate cancer (mCRPC) is dynamic with the application of multiple treatments. The circulating tumor DNA (ctDNA), which reveals germline and somatic alterations, provides a mini-invasive tool for monitoring tumor evolution. Methods: We performed an exploratory analysis of 299 ctDNA samples from 8 centers through application of multiple-gene deep targeted sequencing. Results: The most common recurrent genomic alterations were in AR(34.7%), TP53(18.9%), CDK12(15.4%), BRCA2(13.3%), and the majority of these clinically actionable gene alterations were identified in somatic level (CDK12 100% in somatic). The results showed the frequency of AR amplification and TP53 defect significantly increased in post-second and later line treatment group compared with treatment-naive group. AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi). However, these patients seemed to benefit from chemotherapy, especially platinum-based chemotherapy. Conclusions: This multi-institutional real-world study explored the genomic landscape and captured the significant diversity of mCRPC at different treatment stages by liquid biopsy. These findings established genomic drivers associated with resistance to multiple treatments (including PARPi and platinum-based chemotherapy) in mCRPC. Hence, ctDNA targeted sequencing can help guide clinical decision making in mCRPC throughout the whole treatment process. CDK12 might be able to be a novel predictive biomarker to guide treatment selection in mCRPC.
The role of programmed death-ligand 1 and non-epithelial circulating tumor cells in locally advanced prostate cancer.
Authors: Li Ke , Mao Yunhua , Li Yiyuan , Wu Ruji , Wang Dejuan , Qiu Jianguang 
Published: May 2020

e17557 Background: Circulating tumor cells (CTCs) is considered as an effective prognostic biomarker in malignancies. It is recently recognized that detections of programmed death-ligand 1 (PD-L1) and mesenchymal markers in CTCs may improve the predictive value. Therefore, we aimed to determine the cut-off values of these CTCs biomarkers in prostate cancer (PCa), assess the rates of PD-L1 positive and non-epithelial (NE) subgroup in CTCs among patients with high-risk (HRPC) and locally advanced PCa (LAPC) before surgery, and evaluate the clinical values of these markers. Methods: Four PCa cell lines selected from Cancer Cell Line Encyclopedia were applied in spiking experiments to establish the cut-offs of PD-L1 positive and NE CTCs. 182 HRPC and 89 LAPC patients were enrolled from June 2016 to December 2018. All patients underwent radical prostatectomy after blood sample collection. CTCs enumeration and biomarkers identification were conducted by Canpatrol CTC enrichment system and the RNA in situ hybridization technique. Lastly, using the cut-offs,we evaluated the association between CTCs markers and other variables in terms of clinical data, disease outcome, tumor tissues immunochemistry (IHC) staining, and the response of immunotherapy. Results: The cut-offs were determined as the lowest rates of NE and PD-L1+ CTCs among the cell lines, 45% and 25%, respectively. In HRPC patients, a higher PSA level and more advanced T stage were observed in the NE CTCs positive group (≥45%), compared with the negative group ( P= 0.041 and P= 0.004). Multivariate analysis showed that the NE CTCs rate, instead of total CTCs number, was an independent risk predictor for progression-free survival (PFS) (HR = 3.85, P= 0.013). In LAPC patients, the PD-L1+ CTCs positive group (≥25%) presented a higher PSA level and higher percentage of lymph node metastasis than negative group ( P= 0.027 and P= 0.028). The median PFSs between the two groups were 16.6 mouths vs. 21.8 mouths, respectively. (HR = 2.87, P= 0.002 ). No significant correlation was found between PD-L1 expression in CTCs and in tumor tissue IHC staining. However, we observed a significant correlation between PD-L1+ CTCs rate and ERG or PTEN expression in tissues ( P= 0.010 and P= 0.009). In addition, patients in PD-L1+ CTCs positive group presented a better PSA response to Durvalumab treatment than those in negative group. Conclusions: PD-L1+ and NE CTCs were an effective prognosis predictors for HRPC and LAPC patients with radical prostatectomy. LAPC patients with PD-L1+ CTCs might benefit from adjuvant immunotherapy
Genomic profiles and clinical outcomes to distinguish primary from secondary metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: Nizialek Emily , Lim Su Jin , Wang Hao , Isaacsson Velho Pedro , Antonarakis Emmanuel S. 
Published: May 2020

e17558 Background: Clinical outcomes may differ among pts with primary (de novo) mHSPC vs. secondary (relapsed) mHSPC occurring after previous local therapy. However, it is unknown what molecular features distinguish these potentially distinct presentations. Methods: A single-center retrospective study was performed using pts with mHSPC and available somatic genomic data. Clinicopathologic characteristics were collected, and pts were classified as primary mHSPC (n = 118) or secondary mHSPC (n = 104). A targeted set of genes suspected to influence disease severity and response to systemic therapy was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, combined PTEN/RB1/TP53 alterations (2 out of 3), and a composite of any homologous recombination deficiency (HRD) mutation. Hazard ratios for PFS and OS were compared between groups using the log-rank test. Differences in genomic features and baseline characteristics between groups were compared using Fischer exact and chi-squared tests. Results: Median PFS from initiation of first-line ADT was 16.0 mo and 28.9 mo for men with primary and secondary mHSPC, respectively (HR 0.59, 95% CI 0.43–0.83; P= 0.002). OS did not differ between groups (HR 0.92, 95% CI 0.56–1.52; P= 0.7) There were more men with Gleason 8-10 disease in the primary vs. secondary mHSPC groups (91% vs. 67%, P= < 0.01). In terms of molecular alterations, there were more PTEN and CDK12 mutations in the primary mHSPC group ( PTEN: 27% vs 19%, CDK12: 7% vs 3%), but more BRCA2 mutations in the secondary mHSPC group (5% vs 10%, respectively). In univariate analysis, PTEN mutations (HR 1.39, P= 0.08) and combined PTEN/RB1/TP53 mutations (HR 1.46, P= 0.09) predicted worse PFS; PTEN mutations (HR 1.63, P= 0.09) and combined PTEN/RB1/TP53 mutations (HR 2.38, P= 0.01) also predicted worse OS. In multivariable models adjusting for age at first metastasis and Gleason sum, only combined PTEN/RB1/TP53 mutations were predictive of worse OS (adjusted HR 2.32, 95% CI 1.14–4.71; P= 0.02). Conclusions: Compared to secondary mHSPC, primary mHSPC pts had higher Gleason scores, more frequent PTEN and CDK12 mutations, and less frequent BRCA2 mutations. In our study, such pts demonstrated worse PFS but not OS. While the strongest negative predictor of OS was the presence of combined PTEN/RB1/TP53 mutations, other contributors such as CDK12 and BRCA2 may also partially explain differences in outcomes. Thus, primary mHSPC appears to be clinically and genomically distinct from secondary mHSPC, and may require unique treatment paradigms.
Inflammatory and insulinemic dietary patterns: Influence on circulating biomarkers and prostate cancer risk in the prostate, lung, colorectal and ovarian cancer (PLCO) cohort.
Authors: Aroke Desmond , Folefac Edmund , Jin Qi , Shi Ni , Clinton Steven K. , Tabung Fred 
Published: May 2020

e17561 Background: Prostate cancer (PCa) is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. Methods: First, we examined associations of the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores with circulating concentrations of relevant biomarkers, to assess the validity of these two dietary patterns. Secondly, we investigated associations of the EDIH and EDIP with risk of PCa (total, low-grade, high-grade, advanced and lethal). EDIH and EDIP dietary scores calculated from food frequency questionnaire data for 3,517 men and women who provided a blood sample at enrollment, were used to validate dietary patterns against known relevant biomarkers. A separate sample of 49,317 men was used to evaluate the associations of EDIH and EDIP with prostate cancer risk. We used multivariable-adjusted linear regression to compute the percent change and 95% confidence intervals (95%CI) in biomarker concentrations, and Cox regression to estimate hazard ratios (HR) and 95%CI for PCa risk; in dietary score quintiles, using the lowest quintile as reference. Results: Compared to the lowest quintile, participants in the highest EDIH quintile (most hyperinsulinemic diets) had significantly higher concentrations of C-peptide, insulin, CRP, and TNF-R2 and lower adiponectin. Those consuming the most pro-inflammatory diets (EDIP) had significantly higher concentrations of IL-6, TNF-R2, C-peptide and insulin with lower adiponectin. Men classified in EDIH quintile 5 compared to 1, were also at higher total PCa risk: HR, 1.11; 95%CI, 1.01, 1.23; P-trend = 0.03, especially high-grade cancer: HR, 1.18; 95%CI, 1.02, 1.37; P-trend = 0.06; whereas the EDIP was not associated with risk. Conclusions: EDIH and EDIP predicted concentrations of biomarkers relevant to the insulinemic and inflammatory potential of diet in PLCO. EDIH predicted future PCa risk and may suggest a dietary pattern for PCa prevention.
Phase Ib study assessing different sequencing regimens of atezolizumab (anti-PD-L1) and sipuleucel-T (SipT)in patients who have asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.
Authors: Rosser Charles Joel , Hirasawa Yosuke , Acoba Jared David , Tamura David Jon , Pal Sumanta K. , Huang Jeffrey , Scholz Mark C. , Dorff Tanya B. 
Published: May 2020

e17564 Background: Combining an immune checkpoint inhibitor with a tumor vaccine may leverage complementary mechanisms of action for treatment of mCRPC. Atezolizumab, a fully human anti–PD-L1 IgG1 antibody, is an approved treatment option in multiple indications; while SipT, an autologous cellular immunotherapeutic, is approved for treatment of metastatic castrate resistant prostate cancer (mCRPC). We present a phase Ib study evaluating safety, tolerability and objective response rate of atezolizumab + SipT in patients with mCRPC (NCT03024216). Methods: Eligible patients who had asymptomatic or minimally symptomatic progressive mCRPC and met standard criteria for sipuleucel-T were randomized to receive either atezolizumab 1200 mg IV every 3 weeks for 2 doses then SipT IV every 2 weeks for a total of three infusions (Arm 1) or SipT IV every 2 weeks for a total of three infusions followed by atezolizumab 1200 mg IV every 3 weeks for 2 doses (Arm 2). The primary endpoint was safety, while secondary endpoints included objective tumor response (PCWG2 and modified RECISTv1.1 criteria) and comparing systemic immune responses after induction between the arms. Results: As of February 6, 2020, 37 pts (median follow-up 7.4 months, median age 75 yrs [range 53.0–86.0]; median number of previous treatments 4 [range 1-8], 75.7% ECOG PS = 0) were enrolled. Three patients did not complete induction therapy (1 – withdrew consent, 1 developed toxicity, and 1 progressed). There were no grade 5 toxicities attributed to study drugs and grade 4 toxicities were noted in 2 patients, 1 in each arm (Arm 1 bronchitis and Arm 2 hypotension). Eight grade 3 toxicities were noted in arm 1 (hyponatremia, pulmonary embolus x3, bone pain, hypophosphatemia, shock, tooth fracture from a fall), while 4 grade 3 toxicities were noted in arm 2 (anemia, hypertension x 2, pneumonia). None of the grade 3 or 4 SAEs were noted to be irAEs. At 6 months, there were 11 SD (7 in Arm 1 and 4 in Arm 2), 18 PD and 7 unevaluable (3 withdrew from study and 4 have yet to reach 6 month evaluation). At this time, PFS was noted to be 8.2 months in Arm 1 and 5.8 months in Arm 2 (p = 0.054). Conclusions: The safety profile of the combination of atezolizumab with sipuleucel-T appears manageable in a heavily pre-treated population and consistent with those agents administered as monotherapy. Responses were seen but no CR. Immune activation studies may shed light on which sequence is optimal. Clinical trial information: NCT03024216 .
Effect of modulation of CD3 binding in a PSMAxCD3 T-cell engaging bispecific antibody on maintenance of efficient tumor cell kill and cytokine release.
Authors: Buelow Ben , Dang Kevin , Dalvi Pranjali , Li Yuping , Cheung Alexander , Rancan Chiara , Sankaran Preethi , Pham Duy , Harris Katherine , Davison Laura , Balasubramani Aarti , Clarke Starlynn , Starzinski Alec , Fong Lawrence , Iyer Suhasini 
Published: May 2020

e17583 Background: Castration resistant prostate cancer (CRPC) is an incurable disease and represents a significant unmet need. Prostate specific membrane antigen (PSMA) is a protein highly expressed on the surface of prostate cancer cells; expression has been shown to increase with disease progression. Therapies targeting PSMA, such as anti-PSMA radioligand conjugates, have shown promise in clinical trials, validating this target for CRPC. T-cell recruiting bispecific antibodies (T-BsAbs) have demonstrated potent tumor killing activity against multiple tumor types, but immune-mediated toxicities have hampered T-cell redirecting therapies to date. Using Teneobio’s unique antibody discovery platform, we have developed a CD3xPSMA bispecific antibody (TNB-585) that retains the potent cytotoxicity of other T-BsAbs but with significantly reduced cytokine release. Methods: Antibodies targeting CD3 and PSMA were generated via immunization of our proprietary transgenic animals. Candidate antibodies were selected by repertoire deep sequencing of B-cells from draining lymph nodes, followed by high-throughput gene assembly and recombinant expression. Multiple bispecific antibodies targeting CD3 and PSMA were assembled and evaluated for their ability to selectively activate primary human T-cells and mediate killing of PSMA+ tumor cells in vitro, ex vivo, and in vivo. T-cell activation surface markers, cytokine production, and tumor cell cytotoxicity were measured. Results: In co-culture experiments, primary human T-cells were activated only in the presence of both the bispecifics and PSMA+ cells. These bispecifics mediated potent and selective cytotoxicity against PSMA-positive tumor cells, prostate tumor cell lines, or primary human prostate tumor cells isolated from patients. From among these we identified TNB-585, which showed attenuated binding to CD3. TNB-585 mediated comparable tumor cell cytotoxicity to CD3xPSMA T-BsAbs containing a high affinity anti-CD3 domain but with significantly reduced cytokine production. TNB-585 also showed tumor growth inhibition in xenograft models of prostate cancer in vivo. Conclusions: We have developed a novel CD3xPSMA T-BsAb that mediates T-cell killing of PSMA+ tumor cells with minimal production of cytokines. This molecule may improve safety, efficacy, and offer opportunities for combination therapy to treat CRPC. A Phase 1 clinical trial of this compound in CRPC is scheduled to begin in Q1 2021.
Sipuleucel-T (sip-T) and oral androgen axis inhibitors in black men being treated for metastatic castration-resistance prostate cancer (mCRPC): Observations from the Medicare Fee for Service (FFS) population.
Authors: Borno Hala , Moses Kelvin A. , Monk Paul , Fitch Kate , Harmon Matthew , Flanders Scott , McKay Rana R. 
Published: May 2020

e17589 Background: Black men historically have been underrepresented in clinical trials, contributing to poor understanding of potential race-based differences in prostate cancer care and biology. This retrospective, real world analysis examines survival outcomes in black men who received sip-T or oral agents like abiraterone or enzalutamide for mCRPC. Methods: Using Medicare Fee for Service Identifiable Research data, we identified racially black men with a qualifying prostate cancer diagnosis (ICD-9 185, ICD-10 C-61) and an initial drug claim for treatment (abiraterone acetate, cabazitaxel, docetaxel, enzalutamide, radium-223, or sip-T) in 2014 or 2015. Continuous Part A, B, and D eligibility and no HMO enrollment were required for 24 months or until death per Social Security Death Index. We compared outcomes in black patients who received sip-T at any time vs those who received an oral agent in any line and no sip-T. Survival was estimated using the Kaplan-Meier method (unadjusted) and hazard ratios using Cox proportional hazards regression. Results: Of 14,456 patients identified in 2014 and 2015, 1603 were racially black. Among eligible men, 140 received sip-T and 1266 received an oral agent. At 24 months, 76% of men who received sip-T were still alive compared with 49% of those who received the oral agents (Table). Median OS was not estimable in men who received sip-T but was 23.1 months (95% CI: 21.6, NE) in those who received oral agents (Table). In a univariate model, use of sip-T resulted in a 63% reduction in risk of death compared to never receiving sip-T (HR, 0.37 [95% CI, 0.26, 0.52], P < 0.0001). Conclusions: In this real world analysis of black mCRPC patients, sip-T at any point was associated with longer OS over those receiving the oral agents without ever receiving sip-T. Development of a multivariate model is planned. [Table: see text]
Disease characteristics and outcome of patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received a beta emitter (177Lu-PSMA) after an alpha emitter (radium-223).
Authors: Sartor A. Oliver , la Fougère Christian , Essler Markus , Ezziddin Samer , Kramer Gero , Ellinger Jörg , Nordquist Luke T. , Sylvester John , Paganelli Giovanni , Peer Avivit , Boegemann Martin , Meltzer Jeffrey , Sandstrom Per , Song Danny 
Published: May 2020

e17592 Background: Ra-223, a targeted alpha therapy, showed an overall survival (OS) benefit and favorable safety profile in mCRPC pts in a phase 3 trial. 177Lu-PSMA radioligand is an investigational agent for mCRPC. REASSURE (NCT02141438) is a global, prospective, observational study investigating Ra-223 safety in routine clinical practice over 7 years’ follow-up in mCRPC pts. Data from the second prespecified interim analysis (IA) were used to investigate safety and outcomes of pts who received 177Lu-PSMA after Ra-223 therapy. Methods: Data cut-off for the second prespecified IA was March 2019, and included pts who had subsequent 177Lu-PSMA after the last Ra-223 dose. Disease characteristics, adverse events (AEs) after last Ra-223 dose, and OS are described. Results: Of 1465 pts overall, 26 received 177Lu-PSMA subsequent to Ra-223. In this subgroup, pts received multiple anticancer therapies prior to 177Lu-PSMA. 13 pts (50%) received Ra-223 as combination therapy at second line (metastatic setting). Pts received a median of six Ra-223 doses. After Ra-223 treatment ended, 3 pts (12%) had drug-related serious AEs, 9 pts (35%) had grade 3/4 bone marrow suppression-relevant hematologic AEs. Median duration of 177Lu-PSMA treatment was 3.5 months. 19 pts (73%) received 177Lu-PSMA as fourth-line therapy or onwards. OS was 28.0 months from start of Ra-223 and 13.2 months from start of 177Lu-PSMA. Conclusions: In this select population receiving a sequence of multiple lines of therapy with different modes of action, grade 3/4 hematologic AEs after Ra-223 were low. Treatment with subsequent 177Lu-PSMA seems feasible, based on duration of 177Lu-PSMA and survival. Clinical trial information: NCT02141438 . [Table: see text]