scholarly journals Immunophenotyping reveals longitudinal changes in circulating immune cells during radium-223 therapy in patients with metastatic castration-resistant prostate cancer

2020 ◽  
Author(s):  
J.H.A. Creemers ◽  
M.J. van der Doelen ◽  
S. van Wilpe ◽  
R. Hermsen ◽  
T. Duiveman-de Boer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Castration Resistant Prostate Cancer ◽  
Linear Regression Models ◽  
Castration Resistant ◽  
Radium 223 ◽  
Immunological Mechanisms

ABSTRACTPurposeRadium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.Experimental DesignIn this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.ResultsWe observed a substantial decrease in absolute lymphocyte counts (−0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an ALP response during therapy.ConclusionImmune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.

scholarly journals Immunophenotyping Reveals Longitudinal Changes in Circulating Immune Cells During Radium-223 Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jeroen H. A. Creemers ◽  
Maarten J. van der Doelen ◽  
Sandra van Wilpe ◽  
Rick Hermsen ◽  
Tjitske Duiveman-de Boer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Castration Resistant Prostate Cancer ◽  
Linear Regression Models ◽  
Castration Resistant ◽  
Radium 223 ◽  
Immunological Mechanisms

BackgroundRadium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.Materials and MethodsIn this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.ResultsWe observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an alkaline phosphatase response during therapy.ConclusionImmune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.

Identification of immune cell infiltration pattern and related critical genes in metastatic castration-resistant prostate cancer by bioinformatics analysis

2021 ◽  
pp. 1-15
Author(s):  
Caibin Fan ◽  
Wei Lu ◽  
Kai Li ◽  
Chunchun Zhao ◽  
Fei Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Protein Interaction ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Cell Infiltration ◽  
Castration Resistant Prostate Cancer ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Castration Resistant

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is the lethal stage of prostate cancer and the main cause of morbidity and mortality, which is also a potential target for immunotherapy. METHOD: In this study, using the Approximate Relative Subset of RNA Transcripts (CIBERSORT) online method, we analysed the immune cell abundance ratio of each sample in the mCRPC dataset. The EdgeR (an R package) was used to classify differentially expressed genes (DEGs). Using the Database for annotation, visualisation and interactive exploration (DAVID) online method, we performed functional enrichment analyses. STRING online database and Cytoscape tools have been used to analyse protein-protein interaction (PPI) and classify hub genes. RESULTS: The profiles of immune infiltration in mCRPC showed that Macrophages M2, Macrophages M0, T cells CD4 memory resting, T cells CD8 and Plasma cells were the main infiltration cell types in mCRPC samples. Macrophage M0 and T cell CD4 memory resting abundance ratios were correlated with clinical outcomes. We identified 1102 differentially expressed genes (DEGs) associated with the above two immune cells to further explore the underlying mechanisms. Enrichment analysis found that DEGs were substantially enriched in immune response, cell metastasis, and metabolism related categories. We identified 20 hub genes by the protein-protein interaction network analysis. Further analysis showed that three critical hub genes, CCR5, COL1A1 and CXCR3, were significantly associated with prostate cancer prognosis. CONCLUSION: Our findings revealed the pattern of immune cell infiltration in mCRPC, and identified the types and genes of immune cells correlated with clinical outcomes. A new theoretical basis for immunotherapy may be given by our results.

scholarly journals Early alkaline phosphatase dynamics as biomarker of survival in metastatic castration-resistant prostate cancer patients treated with radium-223

2021 ◽  
Author(s):  
Maarten J. van der Doelen ◽  
Agnes Stockhaus ◽  
Yuanjun Ma ◽  
Niven Mehra ◽  
Jeffrey Yachnin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Alkaline Phosphatase ◽  
Confidence Interval ◽  
Surrogate Marker ◽  
Response Monitoring ◽  
Castration Resistant Prostate Cancer ◽  
Related Event ◽  
Castration Resistant ◽  
Radium 223 ◽  
Skeletal Related Event

Abstract Purpose Radium-223 is a life-prolonging therapy for castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases. However, validated biomarkers for response monitoring are lacking. The study aim was to investigate whether early alkaline phosphatase (ALP) dynamics after the first radium-223 injection can act as surrogate marker for overall survival (OS). Methods This retrospective multicenter study included consecutive CRPC patients treated with radium-223. Patients were divided into four subgroups based on baseline ALP level (normal/elevated) and early ALP response, defined as ≥10% ALP decrease after the first radium-223 injection. Primary endpoint was OS among the subgroups. Secondary endpoints included time to first skeletal-related event, time to ALP progression, and treatment completion rate. Results A total of 180 patients were included for analysis. Median OS was 13.5 months (95% confidence interval 11.5–15.5). Patients with elevated baseline ALP without ALP response after the first injection had significantly worse OS when compared to all other patients (median OS 7.9 months versus 15.7 months, hazard ratio 2.56, 95% confidence interval 1.73–3.80, P < 0.001). Multivariate analysis demonstrated that elevated baseline ALP without ALP response after the first injection, the number of prior systemic therapies, baseline LDH level, and baseline ECOG performance status were prognostic factors of OS. Patients with elevated baseline ALP without ALP response after the first injection had significantly shorter times to ALP progression and first skeletal-related event, and more frequently discontinued radium-223 therapy when compared to other patients. Conclusion Early treatment–induced changes in ALP after one radium-223 injection were associated with OS in metastatic CRPC patients.

Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Silke Gillessen ◽  
Ananya Choudhury ◽  
Alejo Rodriguez-Vida ◽  
Franco Nole ◽  
Enrique Gallardo Diaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Safety Analysis ◽  
Phase Iii ◽  
Fracture Rate ◽  
Castration Resistant Prostate Cancer ◽  
Continuous Administration ◽  
Castration Resistant ◽  
Radium 223 ◽  
Safety Population

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]

scholarly journals Economic Evaluations of Cabazitaxel for Treatment of Post-docetaxel Metastatic Castration-resistant Prostate Cancer: Evidence from a Systematic Review

2019 ◽  
pp. 1-8
Author(s):  
Nikinaz Ashrafi Shahmirzadi ◽  
Pardis Zaboli ◽  
Monireh Afzali ◽  
Bereket Molla Tigabu ◽  
Mirhamed Hajimiri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Cost Effective ◽  
Bibliographic Databases ◽  
Economic Evaluations ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223 ◽  
Number Of Patients ◽  
Effective Option

Background and Objectives: Prostate cancer is an ever-increasing global incidence and has become the fifth leading cause of cancer-related mortality in men. A significant number of patients with prostate cancer develop metastatic castration-resistant prostate cancer (mCRPC). There are a few second-line treatment options for patients with post-docetaxel mCRPC. This systematic review aimed to assess the cost-effectiveness of cabazitaxel for the treatment of mCRPC. Materials and Methods: Electronic bibliographic databases including: PubMed/Medline, NICE, CRD, and Scopus were searched in January 2018 for identifying full economic evaluations published in English and Persian. The risk of assessment bias and descriptive analyses of individual studies’ findings were presented. Results: Three articles that fulfilled the inclusion criteria were included in the current study. All the included records had a reasonable quality. Cabazitaxel was not recommended as the most cost-effective option for the treatment of docetaxel-refractory mCRPC. Abiraterone acetate and radium-223 were the recommended cost-effective treatments for mCRPC treatment. Conclusion: We found that, in general, while cabazitaxel had equal or slightly higher improvement in Quality-adjusted Life Year (QALY) as compared to the alternatives, it incurred a high cost. Despite the inclusion of a few studies in this review, cabazitaxel was not found to be a cost-effective option. Therefore, we recommend full economic evaluations to be conducted in this area.

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