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https://www.readbyqxmd.com/read/29751029/accelerated-wound-healing-by-injectable-star-poly-ethylene-b-poly-propylene-sulfide-scaffolds-loaded-with-poorly-water-soluble-drugs
#1
Suwei Zhu, Shuoran Li, Helena Escuin-Ordinas, Robert Dimatteo, Wexian Xi, Antoni Ribas, Tatiana Segura
Injectable hydrogel matrices take the shape of a wound cavity and serve as scaffold for tissue repair and regeneration. Yet these materials are generally hydrophilic, limiting the incorporation of poorly water soluble, hydrophobic drugs. Here we show this shortcoming is circumvented through a star-shaped amphiphilic block copolymer comprising poly(ethylene glycol) and poly (propylene sulfide). This star-shaped amphiphilic polymer self-assembles in an aqueous medium into a physically stable hydrogel and effectively dissolves hydrophobic molecules delivering them at therapeutic doses...
May 8, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29743667/evaluation-of-pre-analytical-factors-affecting-plasma-dna-analysis
#2
Havell Markus, Tania Contente-Cuomo, Maria Farooq, Winnie S Liang, Mitesh J Borad, Shivan Sivakumar, Simon Gollins, Nhan L Tran, Harshil D Dhruv, Michael E Berens, Alan Bryce, Aleksandar Sekulic, Antoni Ribas, Jeffrey M Trent, Patricia M LoRusso, Muhammed Murtaza
Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29685882/baseline-tumor-size-is-an-independent-prognostic-factor-for-overall-survival-in-patients-with-melanoma-treated-with-pembrolizumab
#3
Richard W Joseph, Jeroen Elassaiss-Schaap, Richard F Kefford, Wen-Jen Hwu, Jedd D Wolchok, Anthony Michael Joshua, Antoni Ribas, F Stephen Hodi, Omid Hamid, Caroline Robert, Adil I Daud, Roxana S Dronca, Peter Hersey, Jeffrey S Weber, Amita Patnaik, Dinesh P de Alwis, Andrea M Perrone, Jin Zhang, Soonmo Peter Kang, Scot W Ebbinghaus, Keaven M Anderson, Tara Gangadhar
PURPOSE: To assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). EXPERIMENTAL DESIGN: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS)...
April 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29674509/antigen-presentation-keeps-trending-in-immunotherapy-resistance
#4
Anusha Kalbasi, Antoni Ribas
Through a gain-of-function kinome screen, MEX3B was identified as a mediator of resistance to T cell immunotherapy not previously identified using CRISPR based screens. MEX3B is a post-transcriptional regulator of HLA-A, validating the critical role of tumor-intrinsic antigen presentation in T cell immunotherapy and indicating a new putative molecular target.
April 19, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29657129/multi-stage-differentiation-defines-melanoma-subtypes-with-differential-vulnerability-to-drug-induced-iron-dependent-oxidative-stress
#5
Jennifer Tsoi, Lidia Robert, Kim Paraiso, Carlos Galvan, Katherine M Sheu, Johnson Lay, Deborah J L Wong, Mohammad Atefi, Roksana Shirazi, Xiaoyan Wang, Daniel Braas, Catherine S Grasso, Nicolaos Palaskas, Antoni Ribas, Thomas G Graeber
Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis...
April 3, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29567705/cancer-immunotherapy-using-checkpoint-blockade
#6
REVIEW
Antoni Ribas, Jedd D Wolchok
The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints...
March 23, 2018: Science
https://www.readbyqxmd.com/read/29510987/genetic-mechanisms-of-immune-evasion-in-colorectal-cancer
#7
Catherine S Grasso, Marios Giannakis, Daniel K Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan A Nowak, Reiko Nishihara, Zhi Rong Qian, Kentaro Inamura, Teppei Morikawa, Katsuhiko Nosho, Gabriel Abril-Rodriguez, Charles Connolly, Helena Escuin-Ordinas, Milan S Geybels, William M Grady, Li Hsu, Siwen Hu-Lieskovan, Jeroen R Huyghe, Yeon Joo Kim, Paige Krystofinski, Mark D M Leiserson, Dennis J Montoya, Brian B Nadel, Matteo Pellegrini, Colin C Pritchard, Cristina Puig-Saus, Elleanor H Quist, Ben J Raphael, Stephen J Salipante, Daniel Sanghoon Shin, Eve Shinbrot, Brian Shirts, Sachet Shukla, Janet L Stanford, Wei Sun, Jennifer Tsoi, Alexander Upfill-Brown, David A Wheeler, Catherine J Wu, Ming Yu, Syed H Zaidi, Jesse M Zaretsky, Stacey B Gabriel, Eric S Lander, Levi A Garraway, Thomas J Hudson, Charles S Fuchs, Antoni Ribas, Shuji Ogino, Ulrike Peters
To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity...
March 6, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29509327/first-person-antoni-ribas-md-phd-the-physician-scientist-from-the-university-of-california-at-los-angeles-researches-how-new-therapies-for-patients-with-advanced-malignant-melanoma-can-help-to-overcome-resistance-to-treatment
#8
https://www.readbyqxmd.com/read/29496879/selective-targeting-of-engineered-t-cells-using-orthogonal-il-2-cytokine-receptor-complexes
#9
Jonathan T Sockolosky, Eleonora Trotta, Giulia Parisi, Lora Picton, Leon L Su, Alan C Le, Akanksha Chhabra, Stephanie L Silveria, Benson M George, Indigo C King, Matthew R Tiffany, Kevin Jude, Leah V Sibener, David Baker, Judith A Shizuru, Antoni Ribas, Jeffrey A Bluestone, K Christopher Garcia
Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal ( ortho ) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts...
March 2, 2018: Science
https://www.readbyqxmd.com/read/29470191/characterization-of-postinfusion-phenotypic-differences-in-fresh-versus-cryopreserved-tcr-engineered-adoptive-cell-therapy-products
#10
Theodore S Nowicki, Helena Escuin-Ordinas, Earl Avramis, Bartosz Chmielowski, Thinle Chodon, Beata Berent-Maoz, Xiaoyan Wang, Paula Kaplan-Lefko, Lili Yang, David Baltimore, James S Economou, Antoni Ribas, Begoña Comin-Anduix
Adoptive cell therapy (ACT) consisting of genetically engineered T cells expressing tumor antigen-specific T-cell receptors displays robust initial antitumor activity, followed by loss of T-cell activity/persistence and frequent disease relapse. We characterized baseline and longitudinal T-cell phenotype variations resulting from different manufacturing and administration protocols in patients who received ACT. Patients with melanoma who enrolled in the F5-MART-1 clinical trial (NCT00910650) received infusions of MART-1 T-cell receptors transgenic T cells with MART-1 peptide-pulsed dendritic cell vaccination...
June 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29467321/development-of-mk-8353-an-orally-administered-erk1-2-inhibitor-in-patients-with-advanced-solid-tumors
#11
Stergios J Moschos, Ryan J Sullivan, Wen-Jen Hwu, Ramesh K Ramanathan, Alex A Adjei, Peter C Fong, Ronnie Shapira-Frommer, Hussein A Tawbi, Joseph Rubino, Thomas S Rush, Da Zhang, Nathan R Miselis, Ahmed A Samatar, Patrick Chun, Eric H Rubin, James Schiller, Brian J Long, Priya Dayananth, Donna Carr, Paul Kirschmeier, W Robert Bishop, Yongqi Deng, Alan Cooper, Gerald W Shipps, Blanca Homet Moreno, Lidia Robert, Antoni Ribas, Keith T Flaherty
BACKGROUND: Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. METHODS: We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001)...
February 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29466364/abnormalities-in-gray-matter-volume-in-patients-with-borderline-personality-disorder-and-their-relation-to-lifetime-depression-a-vbm-study
#12
Salvatore Aguilar-Ortiz, Pilar Salgado-Pineda, Josep Marco-Pallarés, Juan C Pascual, Daniel Vega, Joaquim Soler, Cristina Brunel, Ana Martin-Blanco, Angel Soto, Joan Ribas, Teresa Maristany, Salvador Sarró, Raymond Salvador, Antoni Rodríguez-Fornells, Edith Pomarol-Clotet, Peter J McKenna
BACKGROUND: Structural imaging studies of borderline personality disorder (BPD) have found regions of reduced cortical volume, but these have varied considerably across studies. Reduced hippocampus and amygdala volume have also been a regular finding in studies using conventional volumetric measurement. How far comorbid major depression, which is common in BPD and can also affect in brain structure, influences the findings is not clear. METHODS: Seventy-six women with BPD and 76 matched controls were examined using whole-brain voxel-based morphometry (VBM)...
2018: PloS One
https://www.readbyqxmd.com/read/29449192/association-of-body-mass-index-and-outcomes-in-patients-with-metastatic-melanoma-treated-with-targeted-therapy-immunotherapy-or-chemotherapy-a-retrospective-multicohort-analysis
#13
Jennifer L McQuade, Carrie R Daniel, Kenneth R Hess, Carmen Mak, Daniel Y Wang, Rajat R Rai, John J Park, Lauren E Haydu, Christine Spencer, Matthew Wongchenko, Stephen Lane, Dung-Yang Lee, Mathilde Kaper, Meredith McKean, Kathryn E Beckermann, Samuel M Rubinstein, Isabelle Rooney, Luna Musib, Nageshwar Budha, Jessie Hsu, Theodore S Nowicki, Alexandre Avila, Tomas Haas, Maneka Puligandla, Sandra Lee, Shenying Fang, Jennifer A Wargo, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Paul B Chapman, Jeffrey A Sosman, Dirk Schadendorf, Jean-Jacques Grob, Keith T Flaherty, Dana Walker, Yibing Yan, Edward McKenna, Jeffrey J Legos, Matteo S Carlino, Antoni Ribas, John M Kirkwood, Georgina V Long, Douglas B Johnson, Alexander M Menzies, Michael A Davies
BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy...
March 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29438370/health-related-quality-of-life-impact-of-cobimetinib-in-combination-with-vemurafenib-in-patients-with-advanced-or-metastatic-braf-v600-mutation-positive-melanoma
#14
Brigitte Dréno, Paolo A Ascierto, Victoria Atkinson, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stroyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Caroline Dutriaux, Claus Garbe, Karen Bartley, Thomas Karagiannis, Ilsung Chang, Isabelle Rooney, Daniel O Koralek, James Larkin, Grant A McArthur, Antoni Ribas
BACKGROUND: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600 -mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported. METHODS: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population...
March 20, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29360859/a-kinetic-investigation-of-interacting-stimulated-t-cells-identifies-conditions-for-rapid-functional-enhancement-minimal-phenotype-differentiation-and-improved-adoptive-cell-transfer-tumor-eradication
#15
Jing Zhou, Michael T Bethune, Natalia Malkova, Alexander M Sutherland, Begonya Comin-Anduix, Yapeng Su, David Baltimore, Antoni Ribas, James R Heath
For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differentiation, and response to stimulation hinders the co-optimization of these factors. We report on a biophysical investigation of how the short-term kinetics of T cell functional activation, through molecular stimulation and cell-cell interactions, competes with phenotype differentiation...
2018: PloS One
https://www.readbyqxmd.com/read/29360728/mechanisms-of-resistance-to-pd-1-and-pd-l1-blockade
#16
Theodore S Nowicki, Siwen Hu-Lieskovan, Antoni Ribas
Cancer immunotherapy utilizing blockade of the PD-1/PD-L1 checkpoint has revolutionized the treatment of a wide variety of malignancies, leading to durable therapeutic responses not typically seen with traditional cytotoxic anticancer agents. However, these therapies are ineffective in a significant percentage of patients, and some initial responders eventually develop resistance to these therapies with relapsed disease. The mechanisms leading to both primary and acquired resistance to PD-1/PD-L1 inhibition are varied and can be both multifactorial and overlapping in an individual patient...
January 2018: Cancer Journal
https://www.readbyqxmd.com/read/29358500/pembrolizumab-plus-pegylated-interferon-alfa-2b-or-ipilimumab-for-advanced-melanoma-or-renal-cell-carcinoma-dose-finding-results-from-the-phase-ib-keynote-029-study
#17
Michael B Atkins, F Stephen Hodi, John A Thompson, David F McDermott, Wen-Jen Hwu, Donald P Lawrence, Nancy A Dawson, Deborah J Wong, Shailender Bhatia, Marihella James, Lokesh Jain, Seth Robey, Xinxin Shu, Blanca Homet Moreno, Rodolfo F Perini, Toni K Choueiri, Antoni Ribas
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts...
April 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29336888/lxr-apoe-activation-restricts-innate-immune-suppression-in-cancer
#18
Masoud F Tavazoie, Ilana Pollack, Raissa Tanqueco, Benjamin N Ostendorf, Bernardo S Reis, Foster C Gonsalves, Isabel Kurth, Celia Andreu-Agullo, Mark L Derbyshire, Jessica Posada, Shugaku Takeda, Kimia N Tafreshian, Eric Rowinsky, Michael Szarek, Roger J Waltzman, Elizabeth A Mcmillan, Connie Zhao, Monica Mita, Alain Mita, Bartosz Chmielowski, Michael A Postow, Antoni Ribas, Daniel Mucida, Sohail F Tavazoie
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)-an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial...
February 8, 2018: Cell
https://www.readbyqxmd.com/read/29320474/high-response-rate-to-pd-1-blockade-in-desmoplastic-melanomas
#19
Zeynep Eroglu, Jesse M Zaretsky, Siwen Hu-Lieskovan, Dae Won Kim, Alain Algazi, Douglas B Johnson, Elizabeth Liniker, Ben Kong, Rodrigo Munhoz, Suthee Rapisuwon, Pier Federico Gherardini, Bartosz Chmielowski, Xiaoyan Wang, I Peter Shintaku, Cody Wei, Jeffrey A Sosman, Richard W Joseph, Michael A Postow, Matteo S Carlino, Wen-Jen Hwu, Richard A Scolyer, Jane Messina, Alistair J Cochran, Georgina V Long, Antoni Ribas
Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response...
January 18, 2018: Nature
https://www.readbyqxmd.com/read/29283791/durable-complete-response-after-discontinuation-of-pembrolizumab-in-patients-with-metastatic-melanoma
#20
Caroline Robert, Antoni Ribas, Omid Hamid, Adil Daud, Jedd D Wolchok, Anthony M Joshua, Wen-Jen Hwu, Jeffrey S Weber, Tara C Gangadhar, Richard W Joseph, Roxana Dronca, Amita Patnaik, Hassane Zarour, Richard Kefford, Peter Hersey, Jin Zhang, James Anderson, Scott J Diede, Scot Ebbinghaus, F Stephen Hodi
Purpose Pembrolizumab provides durable antitumor activity in metastatic melanoma, including complete response (CR) in about 15% of patients. Data are limited on potential predictors of CR and patient disposition after pembrolizumab discontinuation after CR. We describe baseline characteristics and long-term follow-up in patients who experienced CR with pembrolizumab in the KEYNOTE-001 study ( ClinicalTrials.gov identifier: NCT01295827). Patients and Methods Patients with ipilimumab-naive or -treated advanced/metastatic melanoma received one of three dose regimens of pembrolizumab...
December 28, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
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