| 1. |
- Forsberg, Elin, et al.
(författare)
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HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy-Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
- 2019
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Ingår i: Cancer Research. - 0008-5472. ; 79:5, s. 899-904
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Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR-T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner. Significance: These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
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| 2. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
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| 3. |
- Hegre, Håvard, 1964-, et al.
(författare)
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ViEWS : A political violence early-warning system
- 2019
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Ingår i: Journal of Peace Research. - : SAGE Publications. - 0022-3433 .- 1460-3578. ; 56:2, s. 155-174
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Tidskriftsartikel (refereegranskat)abstract
- This article presents ViEWS – a political violence early-warning system that seeks to be maximally transparent, publicly available, and have uniform coverage, and sketches the methodological innovations required to achieve these objectives. ViEWS produces monthly forecasts at the country and subnational level for 36 months into the future and all three UCDP types of organized violence: state-based conflict, non-state conflict, and one-sided violence in Africa. The article presents the methodology and data behind these forecasts, evaluates their predictive performance, provides selected forecasts for October 2018 through October 2021, and indicates future extensions. ViEWS is built as an ensemble of constituent models designed to optimize its predictions. Each of these represents a theme that the conflict research literature suggests is relevant, or implements a specific statistical/machine-learning approach. Current forecasts indicate a persistence of conflict in regions in Africa with a recent history of political violence but also alert to new conflicts such as in Southern Cameroon and Northern Mozambique. The subsequent evaluation additionally shows that ViEWS is able to accurately capture the long-term behavior of established political violence, as well as diffusion processes such as the spread of violence in Cameroon. The performance demonstrated here indicates that ViEWS can be a useful complement to non-public conflict-warning systems, and also serves as a reference against which future improvements can be evaluated.
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| 4. |
- Jespersen, Henrik, et al.
(författare)
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Concomitant use of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study): protocol for a multicenter phase II open label study.
- 2019
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in metastatic uveal melanoma. Thus, metastatic uveal melanoma remains a disease with an urgent unmet medical need. Reports of treatment with immune checkpoint inhibitors have thus far been disappointing. Based on animal experiments, it is reasonable to hypothesize that the effect of immunotherapy may be augmented by epigenetic therapy. Proposed mechanisms include enhanced expression of HLA class I and cancer antigens on cancer cells, as well as suppression of myeloid suppressor cells.The PEMDAC study is a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD1 inhibitor pembrolizumab and the class I HDAC inhibitor entinostat in adult patients with metastatic uveal melanoma. Primary endpoint is objective response rate. Eligible patients have histologically confirmed metastatic uveal melanoma, ECOG performance status 0-1, measurable disease as per RECIST 1.1 and may have received any number of prior therapies, with the exception of anticancer immunotherapy. Twenty nine patients will be enrolled. Patients receive pembrolizumab 200mg intravenously every third week in combination with entinostat 5mg orally once weekly. Treatment will continue until progression of disease or intolerable toxicity or for a maximum of 24months.The PEMDAC study is the first trial to assess whether the addition of an HDAC inhibitor to anti-PD1 therapy can yield objective anti-tumoral responses in metastatic UM.ClinicalTrials.gov registration number: NCT02697630 . (Registered 3 March 2016). EudraCT registration number: 2016-002114-50.
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| 5. |
- Muralidharan, Somsundar Veppil, et al.
(författare)
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BET bromodomain inhibitors synergize with ATR inhibitors in melanoma in melanoma.
- 2017
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Ingår i: Cell Death & Disease. - 2041-4889. ; 8:8, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.
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| 6. |
- Aagerup, Ulf, 1969, et al.
(författare)
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Green consumer behavior: Being good or seeming good?
- 2016
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Ingår i: Journal of Product & Brand Management. - Bingley : Emerald Group Publishing Limited. - 1061-0421. ; 25:3, s. 274-284
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Tidskriftsartikel (refereegranskat)abstract
- Purpose This paper aims to expand the emerging field of symbolic green consumer behavior (GCB) by investigating the impact of anticipated conspicuousness of the consumption situation on consumers’ choice of organic products. In addition, the paper also explores whether self-monitoring ability and attention to social comparison information (ATSCI) influence GCB in situations of anticipated high conspicuousness. Design/methodology/approach Two experiments test the study’s hypotheses. Findings The results of both experiments show that the anticipation of conspicuousness has a significant effect on GCB. Moreover, in Experiment 2, this effect is moderated by consumers’ level of ATSCI but not by their self-monitoring ability. Research limitations/implications Because ATSCI significantly interacts with green consumption because of the anticipation of a conspicuous setting, although self-monitoring ability does not, we conclude that social identification is an important determinant of green consumption. Practical implications Marketers who focus on building green brands could consider designing conspicuous consumption situations to increase GCB. Social implications Policymakers could enact change by making the environmental unfriendliness of non-eco-friendly products visible to the public and thus increase the potential for GCB. Originality/value The results validate the emerging understanding that green products are consumed for self-enhancement, but also expand the literature by highlighting that a key motivating factor of GCB is the desire to fit in.
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| 7. |
- Aagerup, Ulf, 1969, et al.
(författare)
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Self-enhancing green consumer behavior
- 2015
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Ingår i: The 10th annual Global Brand Conference, Turku, Finland, April 27-29.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In the last few decades, the topic of environmental sustainability has received much attention within the marketing literature (Powell, 2011, Leonidou et al., 2013). As our world faces many environmental challenges, both large and small, the thought that part of the solution to these problems is in the consumption based arena has become more popular. To steer toward a more environmentally sustainable consumption is thus seen as desirable for many actors in society. However, while the concepts of green, sustainable, or environmental marketing have existed for several decades, the actual results of these initiatives are discouraging from both research and sustainability perspectives (Crane, 2000). There is a vast " attitude - behavior gap" (Moraes et al., 2 012, Carrington et al., 2010, Carrington et al., 2014) which means that although consumers profess to be positively disposed towards organic products, they do not act accordingly. Traditionally, research in this field has focused on how products’ functiona l benefits and consumers’ values and norms affect green consumer behavior (Salazar et al., 2013) . There is however an emerging understanding that consumers may seek more than functional value from their environmentally friendly brands, value like e.g. stat us (Griskevicius et al., 2010) and identity (Sexton and Sexton, 2011). Thus, for green products to be successful it may not be sufficient to only to be good; they must also make their user seem good. While building on the symbolic/expressive meaning of consumption is a commonly accepted idea within brand building (e.g. Park et al., 1986, Aaker, 1997, Fang et al., 2012) , it has received limited attention within the green consumer behavior domain. We propose that from the symbolic consumption perspective, environmentally friendly products that are consumed conspicuously should represent greater value than those that are consumed inconspicuously. Against this background, the purpose of this paper is to investigate if consumers choose environmentally friendly options to a greater extent if the consumption setting is public rather than private consumption situations.
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| 8. |
- Ameur, Adam, et al.
(författare)
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SweGen : a whole-genome data resource of genetic variability in a cross-section of the Swedish population
- 2017
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Ingår i: European Journal of Human Genetics. - : NATURE PUBLISHING GROUP. - 1018-4813 .- 1476-5438. ; 25:11, s. 1253-1260
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.
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| 9. |
- Belgrano, Valerio, et al.
(författare)
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BRAF status as a predictive factor for response in isolated limb perfusion.
- 2019
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Ingår i: International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group. - : Informa UK Limited. - 1464-5157. ; 36:1, s. 511-15
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Tidskriftsartikel (refereegranskat)abstract
- Isolated limb perfusion (ILP) is a treatment option for unresectable in-transit melanoma metastases of the extremities. Approximately two-thirds of the patients have a complete response, and known predictive factors mainly regard tumor burden. In an attempt to identify subgroups with higher response rates, we retrospectively analyzed the predictive value of the BRAF V600E/K mutation for response at our institution.Between January 2012 and December 2017, 98 consecutive patients underwent first-time ILP with melphalan for melanoma in-transit metastases and were included in the study. Data was retrieved from our prospectively kept database. Tumor burden was assessed preoperatively as number of lesions and largest tumor diameter. BRAF status was determined according to clinical routine. Response rates were classified according to WHO criteria.Of the 98 patients included in the analysis, 32 patients had a BRAF V600E/K mutation (33%) and 66 patients were BRAF wild type (wt). There was no difference in age, sex or tumor burden between the groups. Comparing response between BRAF V600E/K mutation and BRAF wt, the overall response rate was 69% vs. 77% (p=.36) and the complete response rate was 47% vs. 52% (p=.67). There was no difference in survival, with a median survival of 47 months.In this consecutive series of patients, BRAF V600E/K mutation was not found to be a significant factor for response or survival following ILP.
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| 10. |
- Belgrano, Valerio, et al.
(författare)
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Response and Toxicity of Repeated Isolated Limb Perfusion (re-ILP) for Patients With In-Transit Metastases of Malignant Melanoma.
- 2019
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Ingår i: Annals of surgical oncology. - : Springer Science and Business Media LLC. - 1534-4681 .- 1068-9265. ; 26:4, s. 1055-1062
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Tidskriftsartikel (refereegranskat)abstract
- Isolated limb perfusion (ILP) is a safe and well-established treatment for in-transit metastases of melanoma. In case of relapse or disease progression, ILP can be repeated (re-ILP). This study aimed retrospectively to analyze a large consecutive series of re-ILP and compare clinical outcomes with first-time ILP.Between 2001 and 2015, 290 consecutive patients underwent 380 ILPs. Of these, 90 were re-ILPs including 68second ILPs, 16 third ILPs, 4 fourth ILPs, and two fifth ILPs. The study evaluated response (using World Health Organization [WHO] criteria), local toxicity (using the Wieberdink scale), and complications (using Clavien-Dindo).The results were compared between the first ILP, the second ILP, and the third to fifth ILP. The overall response rate was respectively 83%, 80% and 68%, with a complete response (CR) rate of 60%, 41%, and 59%. In the re-ILP group, the patients with a CR after the first ILP had a 65% CR rate after the second ILP compared with 8% for the patients without a CR (p=0.001). The risk for local toxicity or complications was not increased after re-ILP. The median overall survival periods were respectively 34, 41, and 93months (p=0.02).As a therapeutic option, ILP can be repeated safely for in-transit metastases of melanoma, achieving similar high response rates without increasing complications or toxicity. Re-ILP is mainly indicated for patients who already had a CR after the first ILP, whereas other treatment options should be considered for primary non-responders.
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