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In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels. On-treatment peripheral biomarker changes showed that BEMPEG + NIVO increased all immune cell subset counts interrogated, including regulatory T cells. This was followed by attenuation of the increase in CD8 + T cells, conventional CD4 + T cells, and systemic interferon gamma levels at later treatment cycles in the combination arm. Changes in tumor biomarkers were comparable between arms. These biomarker results help provide a better understanding of the mechanism of action of BEMPEG + NIVO and may help contextualize the clinical observations from PIVOT IO 001. [ABSTRACT FROM AUTHOR]

We evaluated the prognostic value of hypoalbuminemia in context of various biomarkers at baseline, including clinical, genomic, transcriptomic, and blood-based markers, in patients with metastatic melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anti-CTLA-4 combination therapy (n = 178). An independent validation cohort (n = 79) was used to validate the performance of hypoalbuminemia compared to serum LDH (lactate dehydrogenase) levels. Pre-treatment hypoalbuminemia emerged as the strongest predictor of poor outcome for both OS (HR = 4.01, 95% CI 2.10–7.67, Cox P = 2.63e−05) and PFS (HR = 3.72, 95% CI 2.06–6.73, Cox P = 1.38e−05) in univariate analysis. In multivariate analysis, the association of hypoalbuminemia with PFS was independent of serum LDH, IFN-γ signature expression, TMB, age, ECOG PS, treatment line, treatment type (combination or monotherapy), brain and liver metastasis (HR = 2.76, 95% CI 1.24–6.13, Cox P = 0.0131). Our validation cohort confirmed the prognostic power of hypoalbuminemia for OS (HR = 1.98, 95% CI 1.16–3.38; Cox P = 0.0127) and was complementary to serum LDH in analyses for both OS (LDH-adjusted HR = 2.12, 95% CI 1.2–3.72, Cox P = 0.00925) and PFS (LDH-adjusted HR = 1.91, 95% CI 1.08–3.38, Cox P = 0.0261). In conclusion, pretreatment hypoalbuminemia was a powerful predictor of outcome in ICI in melanoma and showed remarkable complementarity to previously established biomarkers, including high LDH. [ABSTRACT FROM AUTHOR]

Introduction: Sentinel lymph node biopsy (SLNB) is important for staging in patients with primary cutaneous melanoma. Did having previously undergone SLNB also affect outcomes in patients once they have progressed to metastatic melanoma in the era prior to adjuvant therapy? Methods: Data were retrieved from the Dutch Melanoma Treatment Registry, a prospectively collected, nationwide database of patients with unresectable stage IIIC or IV (advanced) melanoma between 2012 and 2018. Melanoma-specific survival (MSS) was compared between patients with advanced cutaneous melanoma, previously treated with a wide local excision (WLE) or WLE combined with SLNB as initial treatment of their primary tumor. Cox regression analyses were used to analyze the influence of different variables on MSS. Results: In total, 2581 patients were included, of whom 1412 were treated with a WLE of the primary tumor alone and 1169 in whom this was combined with SLNB. At a median follow-up of 44 months from diagnosis of advanced melanoma, MSS was significantly longer in patients who had previously undergone SLNB {median 23 months (95% confidence interval [CI] 19–29) vs. 18 months (95% CI 15–20) for patients treated with WLE alone; p = 0.002}. However, multivariate Cox regression did not identify SLNB as an independent favorable prognostic factor for MSS after diagnosis of advanced melanoma. Conclusion: Prior to the availability of adjuvant systemic therapy, once patients have unresectable stage IIIC or IV (advanced) melanoma, there was no difference in disease outcome for patients who were or were not previously staged with SLNB. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to compare image quality and quantitative accuracy of positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) systems with time of flight PET gantries, using phantom and clinical studies.Procedures: Identical phantom experiments were performed on both systems. Calibration, uniformity, and standardized uptake value (SUV) recovery were measured. A clinical PET/CT versus PET/MRI comparison was performed using [(18)F]fluoromethylcholine ([(18)F]FCH).Results: Calibration accuracy and image uniformity were comparable between systems. SUV recovery met EANM/EARL requirements on both scanners. Thirty-four lesions with comparable PET image quality were identified. Lesional SUVmax differences of 4 ± 26% between PET/MRI and PET/CT data were observed (R (2) = 0.79, slope = 1.02). In healthy tissues, PET/MRI-derived SUVs were 16 ± 11% lower than on PET/CT (R (2) = 0.98, slope = 0.86).Conclusion: PET/MRI and PET/CT showed comparable performance with respect to calibration accuracy, image uniformity, and SUV recovery. [(18)F]FCH uptake values for both healthy tissues and lesions corresponded reasonably well between MR- and CT-based systems, but only in regions free of MR-based attenuation artifacts. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the present study is to determine whether uptake of [(18)F]fluoromethylcholine ([(18)F]FCH) in comparison with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) accurately reflects chemotherapy efficacy at the tumor cell level in prostate cancer (PC).Procedures: The effects of docetaxel and cabazitaxel on viable tumor cell number were explored in four PC cell lines. Cellular uptake of [(18)F]FDG and [(18)F]FCH was compared with the effects measured using sulforhodamine B (SRB) assay, cell counting and colony formation assay (CFA), as proximators of viable tumor cell number. Agreement between uptake and cell numbers was assessed by Bland-Altman plots.Results: [(18)F]FCH uptake in all PC cell lines significantly correlated to the cell numbers surviving the respective drug concentrations. Bland-Altman analysis showed that [(18)F]FDG uptake resulted in signal overestimation and higher variability after chemotherapy.Conclusions: [(18)F]FCH uptake correlates well with viable tumor cell numbers remaining after docetaxel and cabazitaxel exposure. Radiolabeled choline is a potential response monitoring biomarker after chemotherapy for PC. [ABSTRACT FROM AUTHOR]

Targeted therapy has significantly improved the perspectives of patients with metastatic renal cell cancer (mRCC). Frequently, these new molecules cause disease stabilization rather than substantial tumor regression. As treatment options expand with the growing number of targeted agents, there is an increasing need for surrogate markers to early assess tumor response. Here, we review the currently available imaging techniques and response evaluation criteria for the assessment of tumor response in mRCC patients. For computed tomography (CT), different criteria are discussed including the Response Evaluation Criteria in Solid Tumors (RECIST), the Choi criteria, the modified Choi criteria, and the size and attenuation CT (SACT) criteria. Functional imaging modalities are discussed, such as dynamic contrast-enhanced CT (DCE-CT), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), dynamic contrast-enhanced ultrasonography (DCE-US), and positron emission tomography (PET). [ABSTRACT FROM AUTHOR]

Mature circulating endothelial cell (CEC) as well as endothelial progenitor populations may reflect the activity of anti-angiogenic agents on tumor neovasculature or even constitute a target for anti-angiogenic therapy. We investigated the behavior of CECs in parallel with hematopoietic progenitor cells (HPCs) in the blood of renal cell cancer patients during sunitinib treatment. We analyzed the kinetics of a specific population of small VEGFR2-expressing CECs (CD45neg/CD34bright), HPCs (CD45dim/CD34bright), and monocytes in the blood of 24 renal cell cancer (RCC) patients receiving 50 mg/day of the multitargeted VEGF inhibitor sunitinib, on a 4-week-on/2-week-off schedule. Blood was taken before treatment (C1D1), on C1D14, C1D28, and on C2D1 before the start of cycle 2. Also plasma VEGF and erythropoietin (EPO) were determined. Remarkably, while CD34bright HPCs and monocytes decreased during treatment, CD34bright CECs increased from 69 cells/ml (C1D1) to 180 cells/ml (C1D14; P = 0.001) and remained high on C1D28. All cell populations recovered to near pre-treatment levels on C2D1. Plasma VEGF and EPO levels were increased on C1D14 and partly normalized to pre-treatment levels on C2D1. In conclusion, opposite kinetics of two circulating CD34bright cell populations, HPCs and small CECs, were observed in sunitinib-treated RCC patients. The increase in CECs is likely caused by sunitinib targeting of immature tumor vessels. [ABSTRACT FROM AUTHOR]

The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands. [ABSTRACT FROM AUTHOR]

The adoptive transfer of in vitro-induced and expanded tumor-specific cytotoxic T lymphocytes (CTL) presents a promising immunotherapeutic approach for the treatment of cancer. The in vitro induction of tumor-reactive CTL requires repeated stimulation of CTL precursors with dendritic cells (DC). To circumvent problems like scarcity of blood DC precursors and donor variability, it would be attractive to use DC from a non-autologous, unlimited source. DCs derived from the human acute myeloid leukemia (AML) cell line MUTZ-3 are attractive candidates since these DCs closely resemble monocyte-derived DC (MoDC) in terms of phenotype and T cell stimulatory capacity. Here we demonstrate that functional CTL clones could be generated against multiple tumor-associated antigens, i.e., human telomerase reverse transcriptase (hTERT), ErbB3-binding protein-1 (Ebp1), carcinoembryonic antigen (CEA) and Her-2/ neu, by stimulating CD8β+ CTL precursors with peptide-loaded allogeneic, HLA-A2-matched MUTZ-3-derived DC. A consistent induction capacity, as determined by MHC tetramer-binding, was found in multiple donors and comparable to autologous peptide-loaded MoDC. Functional characterization at the clonal level revealed the priming of CTL that recognized endogenously processed epitopes on tumor cell lines in an HLA-A2-restricted fashion. Our data indicate that MUTZ-3-derived DC can be used as stimulator cells for in vitro priming and expansion of functional TAA-specific effector CTL. MUTZ-3-derived DCs thus represent a ready and standardized source of allogeneic DC to generate CTL for therapeutic adoptive transfer strategies. [ABSTRACT FROM AUTHOR]

Objectives: Whole body [18F]-fluorodihydrotestosterone positron emission tomography ([18F]FDHT PET) imaging directly targets the androgen receptor and is a promising prognostic and predictive biomarker in metastatic castration-resistant cancer (mCRPC). To optimize [18F]FDHT PET-CT for diagnostic and response assessment purposes, we assessed how count statistics and reconstruction protocol affect its accuracy, repeatability, and lesion detectability. Methods: Whole body [18F]FDHT PET-CT scans were acquired on an analogue PET-CT on two consecutive days in 14 mCRPC patients harbouring a total of 336 FDHT-avid lesions. Images were acquired at 45 min post-injection of 200 MBq [18F]FDHT at 3 min per bed position. List-mode PET data were split on a count-wise basis, yielding two statistically independent scans with each 50% of counts. Images were reconstructed according to current EANM Research Ltd. (EARL1, 4 mm voxel) and novel EARL2 guidelines (4 mm voxel + PSF). Per lesion, we measured SUVpeak, SUVmax, SUVmean, and contrast-to-noise ratio (CNR). SUV was normalized to dose per bodyweight as well as to the parent plasma input curve integral. Variability was assessed with repeatability coefficients (RCs). Results: Count reduction increased liver coefficient of variation from 9.0 to 12.5% and from 10.8 to 13.2% for EARL1 and EARL2, respectively. SUVs of EARL2 images were 12.0–21.7% higher than EARL1. SUVs of 100% and 50% count data were highly correlated (R2 > 0.98; slope = 0.97–1.01; ICC = 0.99–1.00). Intrascan variability was volume-dependent, and count reduction resulted in higher intrascan variability for EARL2 than EARL1 images. Intrascan RCs were lowest for SUVmean (8.5–10.6%), intermediate for SUVpeak (12.0–16.0%), and highest for SUVmax (17.8–22.2%). Count reduction increased test-retest variance non-significantly (p > 0.05) for all SUV types and normalizations. For SUVpeak at 50% of counts, RCs remained < 30% when small lesions were excluded. Splitting data reduced CNR by median 4.6% (interquartile range 1.2–8.7%) and 4.6% (interquartile range 1.2–8.7%) for EARL1 and EARL2 images, respectively. Conclusions: Reducing [18F]FDHT PET acquisition time from 3 min to 1.5 per bed position resulted in a repeatability of SUVpeak (bodyweight) remaining ≤ 30%, which is generally acceptable for response monitoring purposes. However, EARL2 reconstruction was more affected, especially for SUVmax whose repeatability tended to exceed 30%. Lesion detectability was only slightly impaired by reducing acquisition time, which might not be clinically relevant in mCRPC. [ABSTRACT FROM AUTHOR]

In the original publication of the article the following abstract and keywords were inadvertently omitted. [ABSTRACT FROM AUTHOR]