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https://www.readbyqxmd.com/read/30321203/an-approved-in-vitro-approach-to-preclinical-safety-and-efficacy-evaluation-of-engineered-t-cell-receptor-anti-cd3-bispecific-immtac-molecules
#1
Jane Harper, Katherine J Adams, Giovanna Bossi, Debbie E Wright, Andrea R Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Hazel Buchanan, Gabrielle S Le Provost, Zoe Donnellan, Ricardo J Carreira, Samantha J Paston, Luise U Weigand, Martina Canestraro, Joseph P Sanderson, Sophie Botta Gordon-Smith, Kate L Lowe, Karolina A Rygiel, Alex S Powlesland, Annelise Vuidepot, Namir J Hassan, Brian J Cameron, Bent K Jakobsen, Joseph Dukes
Robust preclinical testing is essential to predict clinical safety and efficacy and provide data to determine safe dose for first-in-man studies. There are a growing number of examples where the preclinical development of drugs failed to adequately predict clinical adverse events in part due to their assessment with inappropriate preclinical models. Preclinical investigations of T cell receptor (TCR)-based immunotherapies prove particularly challenging as these biologics are human-specific and thus the conventional testing in animal models is inadequate...
2018: PloS One
https://www.readbyqxmd.com/read/30247463/generation-of-high-throughput-three-dimensional-tumor-spheroids-for-drug-screening
#2
Lesley Mathews Griner, Kalyani Gampa, Toan Do, Huyen Nguyen, David Farley, Christopher J Hogan, Douglas S Auld, Serena J Silver
Cancer cells have routinely been cultured in two dimensions (2D) on a plastic surface. This technique, however, lacks the true environment a tumor mass is exposed to in vivo. Solid tumors grow not as a sheet attached to plastic, but instead as a collection of clonal cells in a three-dimensional (3D) space interacting with their neighbors, and with distinct spatial properties such as the disruption of normal cellular polarity. These interactions cause 3D-cultured cells to acquire morphological and cellular characteristics which are more relevant to in vivo tumors...
September 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/30221046/predictive-role-of-plasmatic-biomarkers-in-advanced-non-small-cell-lung-cancer-treated-by-nivolumab
#3
Adrien Costantini, Catherine Julie, Coraline Dumenil, Zofia Hélias-Rodzewicz, Julie Tisserand, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur
Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/30184441/identification-of-primary-natural-killer-cell-modulators-by-chemical-library-screening-with-a-luciferase-based-functional-assay
#4
Simon Hayek, Nassima Bekaddour, Laurie Besson, Rodolphe Alves de Sousa, Nicolas Pietrancosta, Sébastien Viel, Nikaia Smith, Yves Jacob, Sébastien Nisole, Rupasri Mandal, David S Wishart, Thierry Walzer, Jean-Philippe Herbeuval, Pierre-Olivier Vidalain
Natural killer (NK) cells are essential players of the innate immune response that secrete cytolytic factors and cytokines such as IFN-γ when contacting virus-infected or tumor cells. They represent prime targets in immunotherapy as defects in NK cell functions are hallmarks of many pathological conditions, such as cancer and chronic infections. The functional screening of chemical libraries or biologics would greatly help identify new modulators of NK cell activity, but commonly used methods such as flow cytometry are not easily scalable to high-throughput settings...
September 5, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/30016071/nanocarrier-mediated-chemo-immunotherapy-arrested-cancer-progression-and-induced-tumor-dormancy-in-desmoplastic-melanoma
#5
Qi Liu, Fengqian Chen, Lin Hou, Limei Shen, Xueqiong Zhang, Degeng Wang, Leaf Huang
In desmoplastic melanoma, tumor cells and tumor-associated fibroblasts are the major dominators playing a critical role in the fibrosis morphology as well as the immunosuppressive tumor microenvironment (TME), compromising the efficacy of therapeutic options. To overcome this therapeutic hurdle, we developed an innovative chemo-immunostrategy based on targeted delivery of mitoxantrone (MIT) and celastrol (CEL), two potent medicines screened and selected with the best anticancer and antifibrosis potentials. Importantly, CEL worked in synergy with MIT to induce immunogenic tumor cell death...
August 28, 2018: ACS Nano
https://www.readbyqxmd.com/read/29989092/ccl2-sqstm1-positive-feedback-loop-suppresses-autophagy-to-promote-chemoresistance-in-gastric-cancer
#6
Wenxia Xu, Qi Wei, Mengjiao Han, Bingluo Zhou, Hanying Wang, Jianbing Zhang, Qiang Wang, Jie Sun, Lifeng Feng, Shouyu Wang, Yang Ye, Xian Wang, Jianwei Zhou, Hongchuan Jin
Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29867975/zoledronate-triggers-v%C3%AE-2-t-cells-to-destroy-and-kill-spheroids-of-colon-carcinoma-quantitative-image-analysis-of-three-dimensional-cultures
#7
Serena Varesano, Maria Raffaella Zocchi, Alessandro Poggi
New successful anti-cancer strategies are based on the stimulation of immune reaction against tumors: however, preclinical testing of such treatments is still a challenge. To improve the screening of anti-cancer drugs, three-dimensional (3D) culture systems, including spheroids, have been validated as preclinical models. We propose the spheroid 3D system to test anti-tumor drug-induced immune responses. We show that colorectal carcinoma (CRC) spheroids, generated with the epithelial growth factor (EGF), can be co-cultured with Vδ2 T cells to evaluate the anti-tumor activity of these effector lymphocytes...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29761297/severe-neurologic-complications-of-immune-checkpoint-inhibitors-a-single-center-review
#8
Sarah Mancone, Thomas Lycan, Tamjeed Ahmed, Umit Topaloglu, Andrew Dothard, William J Petty, Roy E Strowd
BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising class of anticancer drugs associated with immune-related adverse events (IRAEs). In registration studies of selected cancer populations, neurologic IRAEs were rare. Post-marketing experience describing their prevalence in clinical practice continues to be reported. METHODS: A retrospective cohort of patients treated at our institution with ICIs from 2005 to 2017 was identified. Patients with new neurologic ICD codes documented during or after ICI treatment were enrolled...
May 14, 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29719628/novel-water-soluble-lignin-derivative-bp-cx-1-identification-of-components-and-screening-of-potential-targets-in-silico-and-in-vitro
#9
Elena I Fedoros, Alexey A Orlov, Alexander Zherebker, Ekaterina A Gubareva, Mikhail A Maydin, Andrey I Konstantinov, Konstantin A Krasnov, Ruben N Karapetian, Ekaterina I Izotova, Sergey E Pigarev, Andrey V Panchenko, Margarita L Tyndyk, Dmitry I Osolodkin, Evgeny N Nikolaev, Irina V Perminova, Vladimir N Anisimov
Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties...
April 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29699936/il-6-family-cytokines-key-inflammatory-mediators-as-biomarkers-and-potential-therapeutic-targets
#10
REVIEW
Nese Unver, Florencia McAllister
IL-6 is a critical cytokine in acute phase response and involved in the pathogenesis of several chronic inflammatory diseases including cancer. Studies have highlighted that levels of IL-6 and its family members can be useful for diagnosis, prognosis of relapse-free survival and recurrence. IL-6 family cytokines have been identified as cancer biomarkers through screening of inflammatory mediators in different fluids including saliva, serum, and bronchoalveolar lavage fluid (BALF). IL-6 can be modulated by chemopreventive drugs, small molecules, monoclonal antibodies and immune checkpoint inhibitors...
June 2018: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/29698433/isolation-and-molecular-characterization-of-novel-glucarpidases-enzymes-to-improve-the-antibody-directed-enzyme-pro-drug-therapy-for-cancer-treatment
#11
Fatma B Rashidi, Alanod D AlQhatani, Sara S Bashraheel, Shabnam Shaabani, Matthew R Groves, Alexander Dömling, Sayed K Goda
Repeated cycles of antibody-directed enzyme pro-drug therapy (ADEPT) and the use of glucarpidase in the detoxification of cytotoxic methotrexate (MTX) are highly desirable during cancer therapy but are hampered by the induced human antibody response to glucarpidase. Novel variants of glucarpidase (formal name: carboxypeptidase G2, CPG2) with epitopes not recognized by the immune system are likely to allow repeated cycles of ADEPT for effective cancer therapy. Towards this aim, over two thousand soil samples were collected and screened for folate hydrolyzing bacteria using folate as the sole carbon source...
2018: PloS One
https://www.readbyqxmd.com/read/29665849/an-innovative-immunotherapeutic-strategy-for-ovarian-cancer-clec10a-and-glycomimetic-peptides
#12
Laura L Eggink, Katherine F Roby, Robert Cote, J Kenneth Hoober
BACKGROUND: Receptors specific for the sugar N-acetylgalactosamine (GalNAc) include the human type II, C-type lectin receptor macrophage galactose-type lectin/C-type lectin receptor family member 10A (MGL/CLEC10A/CD301) that is expressed prominently by human peripheral immature dendritic cells, dendritic cells in the skin, alternatively-activated (M2a) macrophages, and to lesser extents by several other types of tissues. CLEC10A is an endocytic receptor on antigen-presenting cells and has been proposed to play an important role in maturation of dendritic cells and initiation of an immune response...
April 17, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29514083/pi3k-akt-cooperates-with-oncogenic-notch-by-inducing-nitric-oxide-dependent-inflammation
#13
Santiago Nahuel Villegas, Rita Gombos, Lucia García-López, Irene Gutiérrez-Pérez, Jesús García-Castillo, Diana Marcela Vallejo, Vanina Gabriela Da Ros, Esther Ballesta-Illán, József Mihály, Maria Dominguez
The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis...
March 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29510739/measuring-multiple-parameters-of-cd8-tumor-infiltrating-lymphocytes-in-human-cancers-by-image-analysis
#14
Keith E Steele, Tze Heng Tan, René Korn, Karma Dacosta, Charles Brown, Michael Kuziora, Johannes Zimmermann, Brian Laffin, Moritz Widmaier, Lorenz Rognoni, Ruben Cardenes, Katrin Schneider, Anmarie Boutrin, Philip Martin, Jiping Zha, Tobias Wiestler
BACKGROUND: Immuno-oncology and cancer immunotherapies are areas of intense research. The numbers and locations of CD8+ tumor-infiltrating lymphocytes (TILs) are important measures of the immune response to cancer with prognostic, pharmacodynamic, and predictive potential. We describe the development, validation, and application of advanced image analysis methods to characterize multiple immunohistochemistry-derived CD8 parameters in clinical and nonclinical tumor tissues. METHODS: Commercial resection tumors from nine cancer types, and paired screening/on-drug biopsies of non-small-cell lung carcinoma (NSCLC) patients enrolled in a phase 1/2 clinical trial investigating the PD-L1 antibody therapy durvalumab (NCT01693562), were immunostained for CD8...
March 6, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29498669/using-pdx-for-preclinical-cancer-drug-discovery-the-evolving-field
#15
REVIEW
Juliet A Williams
The ability to create patient derived xenografts (PDXs) has evolved considerably from the breakthrough of the development of immune compromised mice. How researchers in drug discovery have utilized PDX of certain cancer types has also changed from traditionally selecting a few models to profile a drug, to opting to assess inter-tumor response heterogeneity by screening across a broad range of tumor models, and subsequently to enable clinical stratification strategies. As with all models and methodologies, imperfections with this approach are apparent, and our understanding of the fidelity of these models continues to expand...
March 2, 2018: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/29477100/diversity-of-brain-metastases-screening-and-management-in-non-small-cell-lung-cancer-in-europe-results-of-the-european-organisation-for-research-and-treatment-of-cancer-lung-cancer-group-survey
#16
Antonin Levy, Corinne Faivre-Finn, Baktiar Hasan, Eleonora De Maio, Anna S Berghoff, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, Mary O'Brien, Martin Reck, Anne-Marie C Dingemans, Silvia Novello, Thierry Berghmans, Benjamin Besse, Lizza Hendriks
BACKGROUND: Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials. METHODS: An EORTC Lung Cancer Group (LCG) online survey containing questions on NSCLC BM screening and treatment was distributed between 16/02/17 and 15/06/17 to worldwide EORTC LCG members, and through several European scientific societies in the thoracic oncology field...
April 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29466296/sarcoma-spheroids-and-organoids-promising-tools-in-the-era-of-personalized-medicine
#17
REVIEW
Gianluca Colella, Flavio Fazioli, Michele Gallo, Annarosaria De Chiara, Gaetano Apice, Carlo Ruosi, Amelia Cimmino, Filomena de Nigris
Cancer treatment is rapidly evolving toward personalized medicine, which takes into account the individual molecular and genetic variability of tumors. Sophisticated new in vitro disease models, such as three-dimensional cell cultures, may provide a tool for genetic, epigenetic, biomedical, and pharmacological research, and help determine the most promising individual treatment. Sarcomas, malignant neoplasms originating from mesenchymal cells, may have a multitude of genomic aberrations that give rise to more than 70 different histopathological subtypes...
February 21, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29443026/a-paired-bead-and-magnet-array-for-molding-microwells-with-variable-concave-geometries
#18
Gi-Hun Lee, Youngjoon Suh, Joong Yull Park
A spheroid culture is a useful tool for understanding cellular behavior in that it provides an in vivo-like three-dimensional environment. Various spheroid production methods such as non-adhesive surfaces, spinner flasks, hanging drops, and microwells have been used in studies of cell-to-cell interaction, immune-activation, drug screening, stem cell differentiation, and organoid generation. Among these methods, microwells with a three-dimensional concave geometry have gained the attention of scientists and engineers, given their advantages of uniform-sized spheroid generation and the ease with which the responses of individual spheroids can be monitored...
January 28, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29421594/dna-damaging-potential-of-ganoderma-lucidum-extracts
#19
COMPARATIVE STUDY
María Soledad Vela Gurovic, Fátima R Viceconte, Marcelo T Pereyra, Maximiliano A Bidegain, María Amelia Cubitto
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum (Lingzhi or Reishi) is a medicinal mushroom historically used in Asian countries to treat a wide variety of diseases and prolong life. In the last years, G. lucidum has been internationally recognized as an effective adjuvant in cancer treatment. Among active components, the most recent research indicates that polysaccharides modulate the immune response favoring the recovery from toxicity of chemo and radiotherapy while triterpenes are cytotoxic to tumoral cells mainly by altering gene expression...
May 10, 2018: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29367376/new-drugs-and-new-toxicities-pembrolizumab-induced-myocarditis
#20
Faisal Inayat, Muhammad Masab, Sorab Gupta, Waqas Ullah
Pembrolizumab is an immune checkpoint inhibitor that significantly improves clinical outcomes in numerous solid organ malignancies. Despite successful therapeutic responses, this new drug comes with a constellation of adverse reactions. Herein, we chronicle the case of a patient with metastatic non-small-cell lung cancer treated with pembrolizumab. After two cycles, he developed new-onset dyspnoea on exertion. Electrocardiogram showed idioventricular rhythm with diffuse ST-segment elevations. Echocardiography revealed severe biventricular cardiac dysfunction...
January 23, 2018: BMJ Case Reports
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