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https://www.readbyqxmd.com/read/28630228/the-achilles-heel-of-cancer-and-its-implications-for-the-development-of-novel-immunotherapeutic-strategies
#1
Kroopa Joshi, Benjamin M Chain, Karl S Peggs, Sergio A Quezada
Over the last century, scientists have embraced the idea of mobilizing antitumor immune responses in patients with cancer. In the last decade, we have seen the rebirth of cancer immunotherapy and its validation in a series of high profile clinical trials following the discovery of several immune-regulatory receptors. Recent studies point toward the tumor mutational load and resulting neoantigen burden as being crucial to tumor cell recognition by the immune system, highlighting a potentially targetable Achilles heel in cancer...
June 19, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28593860/evolving-adoptive-cellular-therapies-in-urological-malignancies
#2
REVIEW
Yien Ning Sophia Wong, Kroopa Joshi, Martin Pule, Karl S Peggs, Charles Swanton, Sergio A Quezada, Mark Linch
Immunotherapies have long been used to treat urological cancers but rarely lead to cure. In the past 5 years, success of immune checkpoint inhibition has led to a resurgence of enthusiasm for immunotherapy in the treatment of solid tumours. Increased understanding of tumour immune biology, technological advancements of gene transfer and cell culture, and improved clinical infrastructures for routine delivery of cell products, has made cell-based immunotherapeutics a real prospect for cancer therapy. These scientific and clinical activities, attempting to exploit the innate and adaptive immune systems for therapeutic gain, are well exemplified by the urological malignancies of renal, bladder, prostate, and penile cancer, a group of anatomically localised diseases, each with a distinct biology and different immunotherapeutic challenges...
June 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28445469/phylogenetic-ctdna-analysis-depicts-early-stage-lung-cancer-evolution
#3
Christopher Abbosh, Nicolai J Birkbak, Gareth A Wilson, Mariam Jamal-Hanjani, Tudor Constantin, Raheleh Salari, John Le Quesne, David A Moore, Selvaraju Veeriah, Rachel Rosenthal, Teresa Marafioti, Eser Kirkizlar, Thomas B K Watkins, Nicholas McGranahan, Sophia Ward, Luke Martinson, Joan Riley, Francesco Fraioli, Maise Al Bakir, Eva Grönroos, Francisco Zambrana, Raymondo Endozo, Wenya Linda Bi, Fiona M Fennessy, Nicole Sponer, Diana Johnson, Joanne Laycock, Seema Shafi, Justyna Czyzewska-Khan, Andrew Rowan, Tim Chambers, Nik Matthews, Samra Turajlic, Crispin Hiley, Siow Ming Lee, Martin D Forster, Tanya Ahmad, Mary Falzon, Elaine Borg, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Dina Hafez, Ashwini Naik, Apratim Ganguly, Stephanie Kareht, Rajesh Shah, Leena Joseph, Anne Marie Quinn, Phil A Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Jason F Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Dahmane Oukrif, Ayse U Akarca, John A Hartley, Helen L Lowe, Sara Lock, Natasha Iles, Harriet Bell, Yenting Ngai, Greg Elgar, Zoltan Szallasi, Roland F Schwarz, Javier Herrero, Aengus Stewart, Sergio A Quezada, Karl S Peggs, Peter Van Loo, Caroline Dive, C Jimmy Lin, Matthew Rabinowitz, Hugo J W L Aerts, Allan Hackshaw, Jacqui A Shaw, Bernhard G Zimmermann, Charles Swanton
The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study...
April 26, 2017: Nature
https://www.readbyqxmd.com/read/28445112/tracking-the-evolution-of-non-small-cell-lung-cancer
#4
Mariam Jamal-Hanjani, Gareth A Wilson, Nicholas McGranahan, Nicolai J Birkbak, Thomas B K Watkins, Selvaraju Veeriah, Seema Shafi, Diana H Johnson, Richard Mitter, Rachel Rosenthal, Max Salm, Stuart Horswell, Mickael Escudero, Nik Matthews, Andrew Rowan, Tim Chambers, David A Moore, Samra Turajlic, Hang Xu, Siow-Ming Lee, Martin D Forster, Tanya Ahmad, Crispin T Hiley, Christopher Abbosh, Mary Falzon, Elaine Borg, Teresa Marafioti, David Lawrence, Martin Hayward, Shyam Kolvekar, Nikolaos Panagiotopoulos, Sam M Janes, Ricky Thakrar, Asia Ahmed, Fiona Blackhall, Yvonne Summers, Rajesh Shah, Leena Joseph, Anne M Quinn, Phil A Crosbie, Babu Naidu, Gary Middleton, Gerald Langman, Simon Trotter, Marianne Nicolson, Hardy Remmen, Keith Kerr, Mahendran Chetty, Lesley Gomersall, Dean A Fennell, Apostolos Nakas, Sridhar Rathinam, Girija Anand, Sajid Khan, Peter Russell, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Jason F Lester, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Stefan Dentro, Philippe Taniere, Brendan O'Sullivan, Helen L Lowe, John A Hartley, Natasha Iles, Harriet Bell, Yenting Ngai, Jacqui A Shaw, Javier Herrero, Zoltan Szallasi, Roland F Schwarz, Aengus Stewart, Sergio A Quezada, John Le Quesne, Peter Van Loo, Caroline Dive, Allan Hackshaw, Charles Swanton
BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy...
June 1, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28410988/fc-optimized-anti-cd25-depletes-tumor-infiltrating-regulatory-t-cells-and-synergizes-with-pd-1-blockade-to-eradicate-established-tumors
#5
Frederick Arce Vargas, Andrew J S Furness, Isabelle Solomon, Kroopa Joshi, Leila Mekkaoui, Marta H Lesko, Enrique Miranda Rota, Rony Dahan, Andrew Georgiou, Anna Sledzinska, Assma Ben Aissa, Dafne Franz, Mariana Werner Sunderland, Yien Ning Sophia Wong, Jake Y Henry, Tim O'Brien, David Nicol, Ben Challacombe, Stephen A Beers, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry A Chester, Martin Pule, Jeffrey V Ravetch, Teresa Marafioti, Karl S Peggs, Sergio A Quezada
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models...
April 18, 2017: Immunity
https://www.readbyqxmd.com/read/28374777/corrigendum-interleukin-12-bypasses-common-gamma-chain-signalling-in-emergency-natural-killer-cell-lymphopoiesis
#6
Isabel Ohs, Maries van den Broek, Kathrin Nussbaum, Christian Münz, Sebastian J Arnold, Sergio A Quezada, Sonia Tugues, Burkhard Becher
No abstract text is available yet for this article.
April 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28212753/the-trail-induced-cancer-secretome-promotes-a-tumor-supportive-immune-microenvironment-via-ccr2
#7
Torsten Hartwig, Antonella Montinaro, Silvia von Karstedt, Alexandra Sevko, Silvia Surinova, Ankur Chakravarthy, Lucia Taraborrelli, Peter Draber, Elodie Lafont, Frederick Arce Vargas, Mona A El-Bahrawy, Sergio A Quezada, Henning Walczak
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages...
February 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28134623/a-ccr4-antagonist-reverses-the-tumor-promoting-microenvironment-of-renal-cancer
#8
Chiara Berlato, Moddasar N Khan, Tiziana Schioppa, Richard Thompson, Eleni Maniati, Anne Montfort, Maryam Jangani, Monica Canosa, Hagen Kulbe, Urs B Hagemann, Alexander R Duncan, Laura Fletcher, Robert W Wilkinson, Thomas Powles, Sergio A Quezada, Frances R Balkwill
Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell infiltrate and blood chemokine levels...
March 1, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28002729/the-heterogeneity-of-ly6c-hi-monocytes-controls-their-differentiation-into-inos-macrophages-or-monocyte-derived-dendritic-cells
#9
Shinelle Menezes, Daisy Melandri, Giorgio Anselmi, Thibaut Perchet, Jakob Loschko, Juan Dubrot, Rajen Patel, Emmanuel L Gautier, Stéphanie Hugues, M Paula Longhi, Jake Y Henry, Sergio A Quezada, Grégoire Lauvau, Ana-Maria Lennon-Duménil, Enrique Gutiérrez-Martínez, Alain Bessis, Elisa Gomez-Perdiguero, Christian E Jacome-Galarza, Hannah Garner, Frederic Geissmann, Rachel Golub, Michel C Nussenzweig, Pierre Guermonprez
Inflammation triggers the differentiation of Ly6C(hi) monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3(+)CD11c(-)MHCII(+)PU.1(hi) subset...
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/28002724/too-much-of-a-good-thing-chronic-ifn-fuels-resistance-to-cancer-immunotherapy
#10
James L Reading, Sergio A Quezada
Immune checkpoint blockade (ICB) is revolutionizing cancer medicine, yet the molecular basis of resistance remains unclear. In a recent issue of Cell, Benci et al. (2016) demonstrate that sustained interferon signaling is central to the development of PD-L1-dependent and -independent resistance to ICB.
December 20, 2016: Immunity
https://www.readbyqxmd.com/read/27982126/interleukin-12-bypasses-common-gamma-chain-signalling-in-emergency-natural-killer-cell-lymphopoiesis
#11
Isabel Ohs, Maries van den Broek, Kathrin Nussbaum, Christian Münz, Sebastian J Arnold, Sergio A Quezada, Sonia Tugues, Burkhard Becher
Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122(+)CD49b(+) cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM)...
December 16, 2016: Nature Communications
https://www.readbyqxmd.com/read/27622041/immunomodulatory-antibodies-for-the-treatment-of-lymphoma-report-on-the-calym-workshop
#12
Roch Houot, Philippe Gaulard, Robert Schreiber, Ira Mellman, Olivier Lambotte, Pierre G Coulie, Thierry Fest, Alan Korman, Ronald Levy, Margaret Shipp, Karin Tarte, Holbrook Kohrt, Aurélien Marabelle, Stephen Ansell, Hervé Watier, Andrea van Elsas, Arun Balakumaran, Frederick Arce Vargas, Sergio A Quezada, Gilles Salles, Daniel Olive
In November 2015, the CALYM Carnot Institute held a 2-d workshop to discuss the current and future development of immunomodulatory antibodies for the treatment of lymphoma. Highlights from the workshop are presented in this article.
July 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27571370/large-scale-detection-of-antigen-specific-t-cells-using-peptide-mhc-i-multimers-labeled-with-dna-barcodes
#13
Amalie Kai Bentzen, Andrea Marion Marquard, Rikke Lyngaa, Sunil Kumar Saini, Sofie Ramskov, Marco Donia, Lina Such, Andrew J S Furness, Nicholas McGranahan, Rachel Rosenthal, Per Thor Straten, Zoltan Szallasi, Inge Marie Svane, Charles Swanton, Sergio A Quezada, Søren Nyboe Jakobsen, Aron Charles Eklund, Sine Reker Hadrup
Identification of the peptides recognized by individual T cells is important for understanding and treating immune-related diseases. Current cytometry-based approaches are limited to the simultaneous screening of 10-100 distinct T-cell specificities in one sample. Here we use peptide-major histocompatibility complex (MHC) multimers labeled with individual DNA barcodes to screen >1,000 peptide specificities in a single sample, and detect low-frequency CD8 T cells specific for virus- or cancer-restricted antigens...
October 2016: Nature Biotechnology
https://www.readbyqxmd.com/read/27349975/neoantigen-heterogeneity-a-key-driver-of-immune-response-and-sensitivity-to-immune-checkpoint-blockade
#14
Andrew Js Furness, Sergio A Quezada, Karl S Peggs
No abstract text is available yet for this article.
June 2016: Immunotherapy
https://www.readbyqxmd.com/read/27197251/talen-mediated-inactivation-of-pd-1-in-tumor-reactive-lymphocytes-promotes-intratumoral-t-cell-persistence-and-rejection-of-established-tumors
#15
Laurie Menger, Anna Sledzinska, Katharina Bergerhoff, Frederick Arce Vargas, Julianne Smith, Laurent Poirot, Martin Pule, Javier Hererro, Karl S Peggs, Sergio A Quezada
Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern...
April 15, 2016: Cancer Research
https://www.readbyqxmd.com/read/26940869/clonal-neoantigens-elicit-t-cell-immunoreactivity-and-sensitivity-to-immune-checkpoint-blockade
#16
Nicholas McGranahan, Andrew J S Furness, Rachel Rosenthal, Sofie Ramskov, Rikke Lyngaa, Sunil Kumar Saini, Mariam Jamal-Hanjani, Gareth A Wilson, Nicolai J Birkbak, Crispin T Hiley, Thomas B K Watkins, Seema Shafi, Nirupa Murugaesu, Richard Mitter, Ayse U Akarca, Joseph Linares, Teresa Marafioti, Jake Y Henry, Eliezer M Van Allen, Diana Miao, Bastian Schilling, Dirk Schadendorf, Levi A Garraway, Vladimir Makarov, Naiyer A Rizvi, Alexandra Snyder, Matthew D Hellmann, Taha Merghoub, Jedd D Wolchok, Sachet A Shukla, Catherine J Wu, Karl S Peggs, Timothy A Chan, Sine R Hadrup, Sergio A Quezada, Charles Swanton
As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1...
March 25, 2016: Science
https://www.readbyqxmd.com/read/26578451/negative-immune-checkpoints-on-t-lymphocytes-and-their-relevance-to-cancer-immunotherapy
#17
REVIEW
Anna Śledzińska, Laurie Menger, Katharina Bergerhoff, Karl S Peggs, Sergio A Quezada
The term 'inhibitory checkpoint' refers to the broad spectrum of co-receptors expressed by T cells that negatively regulate T cell activation thus playing a crucial role in maintaining peripheral self-tolerance. Co-inhibitory receptor ligands are highly expressed by a variety of malignancies allowing evasion of anti-tumour immunity. Recent studies demonstrate that manipulation of these co-inhibitory pathways can remove the immunological brakes that impede endogenous immune responses against tumours. Antibodies that block the interactions between co-inhibitory receptors and their ligands have delivered very promising clinical responses, as has been shown by recent successful trials targeting the CTLA-4 and PD-1 pathways...
December 2015: Molecular Oncology
https://www.readbyqxmd.com/read/26508783/talen-mediated-genetic-inactivation-of-the-glucocorticoid-receptor-in-cytomegalovirus-specific-t-cells
#18
Laurie Menger, Agnes Gouble, Maria A V Marzolini, Annette Pachnio, Katharina Bergerhoff, Jake Y Henry, Julianne Smith, Martin Pule, Paul Moss, Stanley R Riddell, Sergio A Quezada, Karl S Peggs
Cytomegalovirus (CMV) infection is responsible for substantial morbidity and mortality after allogeneic hematopoietic stem cell transplant. T-cell immunity is critical for control of CMV infection, and correction of the immune deficiency induced by transplant is now clinically achievable by the adoptive transfer of donor-derived CMV-specific T cells. It is notable, however, that most clinical studies of adoptive T- cell therapy exclude patients with graft-versus-host disease (GVHD) from receiving systemic corticosteroid therapy, which impairs cellular immunity...
December 24, 2015: Blood
https://www.readbyqxmd.com/read/26450984/cord-blood-t-cells-mediate-enhanced-antitumor-effects-compared-with-adult-peripheral-blood-t-cells
#19
Prashant Hiwarkar, Waseem Qasim, Ida Ricciardelli, Kimberly Gilmour, Sergio Quezada, Aurore Saudemont, Persis Amrolia, Paul Veys
Unrelated cord blood transplantation (CBT) without in vivo T-cell depletion is increasingly used to treat high-risk hematologic malignancies. Following T-replete CBT, naïve CB T cells undergo rapid peripheral expansion with memory-effector differentiation. Emerging data suggest that unrelated CBT, particularly in the context of HLA mismatch and a T-replete graft, may reduce leukemic relapse. To study the role of CB T cells in mediating graft-versus-tumor responses and dissect the underlying immune mechanisms for this, we compared the ability of HLA-mismatched CB and adult peripheral blood (PB) T cells to eliminate Epstein-Barr virus (EBV)-driven human B-cell lymphoma in a xenogeneic NOD/SCID/IL2rg(null) mouse model...
December 24, 2015: Blood
https://www.readbyqxmd.com/read/26343581/cyclooxygenase-dependent-tumor-growth-through-evasion-of-immunity
#20
Santiago Zelenay, Annemarthe G van der Veen, Jan P Böttcher, Kathryn J Snelgrove, Neil Rogers, Sophie E Acton, Probir Chakravarty, Maria Romina Girotti, Richard Marais, Sergio A Quezada, Erik Sahai, Caetano Reis e Sousa
The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood. Here, we show that the growth of tumors formed by mutant Braf(V600E) mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation. Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways...
September 10, 2015: Cell
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