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Enhanced silicate weathering, the application of crushed calcium and magnesium-rich rocks to arable cropland, has been proposed as a potential negative emissions technology for the drawdown of atmospheric CO2. Previous estimates have suggested that enhanced silicate weathering (EW) has the potential to remove significant quantities of CO2, as much as 6–30 Mt CO2 yr−1 for the UK. However, if secondary carbonates are precipitated during the riverine transport of the products of EW, a portion of this CO2 will be re-released, lowering the net carbon dioxide removal (CDR) potential of the mitigation strategy. Here, we assess the fluvial response to EW in the UK by calculating the expected riverine carbonate precipitation due to the dissolution of 10–50tha−1 yr−1 of silicate rock on available arable cropland in major UK catchments. Increases in calcite saturation due to the export of soluble cations sourced from EW from soil to rivers are simulated to cross thresholds for spontaneous carbonate precipitation in several major UK river catchments (e.g. the Great Ouse, Thames). Catchments most susceptible to potential secondary carbonate precipitation are those with a high ratio of cropland to water discharge. On average, carbonate precipitation for major UK catchments is expected to make EW 16% (10tha−1), 21% (20tha−1) or 27% (50tha−1) less effective at removing CO2 than that predicted in the absence of such precipitation. Furthermore, when placing strict silica limitations on weathering reactions within soils, the CDR potential of EW is reduced considerably, to 0.23 Mt CO2 yr−1. Although reducing the CDR potential of EW, we suggest that under rapid weathering conditions, carbonate precipitation in UK rivers will prevent pH increases over the safe level for freshwater ecosystems (pH > 9). Together, the simulations suggest that ambient hydrological conditions may make certain UK agricultural areas less effective for CDR by EW and call for methods to quantify secondary carbonate precipitation in response to EW treatments and to further investigate the role of silica saturation in suppressing weathering reactions.

Background The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. Methods This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. Results An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. Conclusion This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations. Electronic supplementary material The online version of this article (10.1186/s40425-019-0632-y) contains supplementary material, which is available to authorized users.

Kevin J Harrington,1 Olivier Michielin,2 Josep Malvehy,3,4 Isabella Pezzani Grüter,5 Lorna Grove,6 Anna Lisa Frauchiger,7 Reinhard Dummer7 1NIHR Biomedical Research Centre, The Institute of Cancer Research/The Royal Marsden Hospital, London, UK; 2Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 3Hospital Clinic de Barcelona, IDIBAPS, CIBER de enfermedades raras, Barcelona, Spain; 4FIS del Instituto de Salud Carlos III, Madrid, Spain; 5Department of Research and Development, Amgen Switzerland AG, Zug, Switzerland; 6Head and Neck Unit, The Royal Marsden Hospital, London, UK; 7Skin Cancer Centre/Dermatology Clinic, Universitätsspital Zürich, Zurich, Switzerland Abstract: Talimogene laherparepvec is a herpes simplex virus-1-based intralesional oncolytic immunotherapy and is the first oncolytic virus to be approved in Europe. It is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stageIIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Talimogene laherparepvec is a genetically modified viral therapy, and its handling needs special attention due to its deep freeze, cold-chain requirements, its potential for viral shedding, and its administration by direct intralesional injection. This review provides a practical overview of handling, storage, and administration procedures for this agent in Europe. Talimogene laherparepvec vials should be transported/stored frozen at a temperature of –90°C to –70°C, and once thawed, vials must not be refrozen. Universal precautions for preparation, administration, and handling should be followed to avoid accidental exposure. Health care providers should wear personal protective equipment, and materials that come into contact with talimogene laherparepvec should be disposed of in accordance with local institutional procedures. Individuals who are immunocompromised or pregnant should not prepare or administer this agent. Talimogene laherparepvec is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Treatment should be continued for ≥6 months. As with other immunotherapies, patients may experience an increase in the size of existing lesion(s) or the appearance of new lesions (ie, progression) prior to achieving a response (“pseudo-progression”). As several health care professionals (eg, physicians [dermatologists, surgeons, oncologists, radiologists], pharmacists, nurses) are involved in different stages of the process, there is a need for good interdisciplinary collaboration when using talimogene laherparepvec. Although there are specific requirements for this agent’s storage, handling, administration, and disposal, these can be effectively managed in a real-world clinical setting through the implementation of training programs and straightforward standard operating procedures. Keywords: herpes simplex virus, intralesional injection, melanoma, oncolytic immunotherapy, practical considerations, talimogene laherparepvec

A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity., Jennings et al., demonstrate that oncolytic HSVGM-CSF activates NK cells and matures immature dendritic cells to promote cytotoxic T lymphocyte (CTL) priming. Moreover, they report that histone deacetylase inhibition can augment innate and adaptive anti-tumor immune responses through increased expression of NK cell-activating ligands and tumor-associated antigens.

Kevin J Harrington,1 Robert HI Andtbacka,2 Frances Collichio,3 Gerald Downey,4 Lisa Chen,5 Zsolt Szabo,6 Howard L Kaufman7 1The Institute of Cancer Research/The Royal Marsden Hospital NIHR Biomedical Research Centre, London, UK; 2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 3Division of Hematology and Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Amgen Ltd, Cambridge, UK; 5Amgen Inc, Thousand Oaks, CA, USA; 6Amgen GmbH, Zug, Switzerland; 7Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA Objectives: Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), talimogene laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio) to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit–risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB–IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P

Stage and grade of transitional cell carcinoma are currently the most useful tools for taking therapeutic decisions and evaluating the prognosis of bladder cancer patients. However, as there are remarkable differences in biological behavior and “biological potential” of tumors classified in the same stage, it is very difficult to predict which superficial tumors will recur and which tumors will give distant metastases. During the last two decades, the better understanding of the molecular mechanisms involved in carcinogenesis and tumor progression has provided a large number of molecular markers of bladder cancer, with a potential diagnostic and prognostic value. This article reviews comprehensively the molecular role and evaluates the clinical significance and the perspectives of these molecular markers. We concluded that, although at the moment there is not a single marker able to predict with accuracy the biological potential of bladder cancer, the most promising markers, at this point, are deletions of chromosome 9, and the tumor suppressor gene p53. Clinical studies are in progress for the assessment of other biological molecules with prognostic potential, such as the E-cadherin, the protein p120, and the telomerase.

Objectives. To investigate the expression of heat shock protein-70 (HSP-70) in transitional cell bladder cancer and correlate it with normal and inflammatory bladder tissue samples. Methods. We used a three-step avidin-biotin method to examine the localization of a rabbit anti-HSP-70 polyclonal antibody in normal (n = 10), inflammatory (n = 10), and malignant (n = 67) bladder tissue samples. Results. Fifty-eight percent of the bladder cancer samples and only 10% and 20% of the normal and inflammatory bladder tissue samples, respectively, expressed HSP-70. Localization of the antibody correlated with the grade (P

Conventional cytotoxic management of leukemia has less than optimal results, while it is associated,vith life-threatening toxic effects due to lack of specificity for hematopoietic cells. Therefore, novel therapeutic strategies with monoclonal antibodies (MAbs) are being explored for delivering chemotherapy or radiation directly to malignant cells. Recently, anti-CD33 antibodies have been engineered to target malignant myeloid and immature normal cells and have been used to deliver cytotoxic agents or radiation to leukemic cells. 131I-labeled anti-CD45 antibodies are used in combination with conventional chemotherapy in leukemic patients receiving marrow transplantation. Additionally, the emergence of Rituximab (against CD20) and Campath-1H (against CD52) for chronic lymphocytic leukemia (CLL) has provided encouraging clinical results for the prognosis of this disease. In conclusion, there has been ongoing research indicating that the approach of patients with leukemia through the application of MAbs might be safer and more effective than current treatment. Considering the preliminary data, MAb therapy appears to be a new, promising weapon in the oncologist’s armentarium.

Background-Human chorionic gonadotropin (hCG) is normally produced and secreted by trophoblastic cells during pregnancy and from gestational trophoblastic neoplasms. It is also detected in ovarian, stomach, and colon adenocarcinomas, as well as in squamous cell carcinoma of the oesophagus. Recently, interest in its role in the pathogenesis of tumours has been enlivened after the presence of beta hCG in the cell membrane of several malignant cells was shown in vitro. Aims-To investigate the circulating concentrations of beta hCG in patients with exocrine pancreatic adenocarcinoma and to examine its potential prognostic value. Patients-Thirty six patients with exocrine pancreatic adenocarcinoma, 12 patients with chronic pancreatitis, and 21 healthy volunteers were studied. Methods-beta hCG serum concentrations were detected by the application of a radioimmunoassay technique. Results-Fifteen of 36 patients with panadenocarcinoma and only one patient with chronic pancreatitis had detectable plasma concentrations of beta hCG (p

PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Immunotherapy; Pembrolizumab; Quality of life Inmunoterapia; Pembrolizumab; Calidad de vida Immunoteràpia; Pembrolizumab; Qualitat de vida Objectives To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). Materials and Methods HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. Results Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. Conclusions Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.