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https://www.readbyqxmd.com/read/28637024/tumor-location-impacts-immune-response-in-mouse-models-of-colon-cancer
#1
Xianda Zhao, Lihua Li, Timothy K Starr, Subbaya Subramanian
Existing preclinical models of human colorectal cancer (CRC) that rely on syngeneic subcutaneous grafts are problematic, because of increasing evidence that the immune microenvironment in subcutaneous tissue is significantly different from the gastrointestinal tract. Similarly, existing orthotopic models that use a laparotomy for establishing grafts are also problematic, because the surgical procedure results in extensive inflammation, thereby creating a nonphysiologic tumor microenvironment. To facilitate the bench-to-bedside translation of CRC immunotherapy strategies, we developed a novel orthotopic model in mice that uses endoscopy-guided microinjection of syngeneic cancer cells...
June 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28635644/pd-1-pd-l1-blockade-therapy-for-tumors-with-downregulated-mhc-class-i-expression
#2
REVIEW
Michal Šmahel
The therapy of different advanced-stage malignancies with monoclonal antibodies blocking programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) signaling has had an impressive long-lasting effect in a portion of patients, but in most cases, this therapy was not successful, or a secondary resistance developed. To enhance its efficacy in treated patients, predictive biomarkers are searched for and various combination treatments are intensively investigated. As the downregulation of major histocompatibility complex (MHC) class I molecules is one of the most frequent mechanisms of tumor escape from the host's immunity, it should be considered in PD-1/PD-L1 checkpoint inhibition...
June 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28635639/immune-checkpoints-as-a-target-for-colorectal-cancer-treatment
#3
REVIEW
Alessandro Passardi, Matteo Canale, Martina Valgiusti, Paola Ulivi
Anti-tumor immunity is a new line of research for the treatment of patients with solid tumors. In this field, negative regulators of the immune system called immune checkpoints play a key role in limiting antitumor immunologic responses. For this reason, immune checkpoint-inhibiting agents, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 receptor (PD1) and its ligand PD-L1, have been developed as antitumor drugs, producing interesting results in preclinical and clinical studies...
June 21, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28634284/co-administration-of-rankl-and-ctla4-antibodies-enhances-lymphocyte-mediated-anti-tumor-immunity-in-mice
#4
Elizabeth Ahern, Heidi Harjunpaa, Deborah Barkauskas, Stacey Allen, Kazuyoshi Takeda, Hideo Yagita, David Wyld, William C Dougall, Michele W L Teng, Mark J Smyth
Purpose: Novel partners for established immune checkpoint inhibitors in the treatment of cancer are needed to address the problems of primary and acquired resistance. The efficacy of combination RANKL and CTLA4 blockade in anti-tumor immunity has been suggested by recent case reports in melanoma. Here we provide a rationale for this combination in mouse models of cancer. <br />Experimental Design: The efficacy and mechanism of a combination of RANKL and CTLA4 blockade was examined by tumor infiltrating lymphocyte analysis, tumor growth and metastasis using a variety of neutralizing antibodies and gene-targeted mice...
June 20, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28634245/targeting-nectin-4-in-bladder-cancer
#5
(no author information available yet)
Preliminary findings from a phase I clinical trial indicate that enfortumab vedotin, an investigational antibody-drug conjugate targeting nectin-4, shows considerable efficacy in metastatic urothelial carcinoma. Robust responses were seen even among patients with disease progression on platinum chemotherapy and/or immune checkpoint blockade.
June 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28634215/vaccination-with-high-affinity-epitopes-impairs-antitumor-efficacy-by-increasing-pd-1expression-on-cd8-t-cells
#6
Christopher D Zahm, Viswa Colluru, Douglas G McNeel
Antitumor vaccines encoding self-antigens generally have low immunogenicity in clinical trials. Several approaches are aimed at improving vaccine immunogenicity, including efforts to alter encoded epitopes. Immunization with epitopes altered for increased affinity for the major histocompatibility complex (MHC) or T-cell receptor (TCR) elicits greater numbers of CD8 T cells but inferior antitumor responses. Our previous results suggested that programmed death 1 (PD-1) and its ligand (PD-L1) increased on antigen-specific CD8 T cells and tumor cells, respectively, after high-affinity vaccination...
June 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28634022/goals-and-objectives-of-the-italian-network-for-tumor-biotherapy-nibit
#7
Vincenzo Russo, Alberto Amadori, Marco Bregni, Luana Calabrò, Mario Paolo Colombo, Massimo Di Nicola, Pier Francesco Ferrucci, Enrico Proietti, Michele Maio, Matteo Bellone
The explosion in the immuno-oncology field, exemplified by the clinical implementation of immune checkpoint inhibitor blockade and other immunotherapeutic strategies was quickly recognized by the Italian biomedical community, thanks to the networking activities of the Italian Network for Tumor Biotherapy (NIBIT), which has been active since 2004 in the diffusion of new scientific and clinical findings in the fields of tumor immunology and immunotherapy. Numerous activities of NIBIT have also helped to overcome the hurdles associated with the clinical implementation of cancer immune-biotherapeutic strategies at the national and international levels...
June 16, 2017: Cytokine & Growth Factor Reviews
https://www.readbyqxmd.com/read/28630051/dna-damage-and-repair-biomarkers-of-immunotherapy-response
#8
REVIEW
Kent W Mouw, Michael S Goldberg, Panagiotis A Konstantinopoulos, Alan D D'Andrea
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies...
June 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28629632/rationale-for-immunological-approaches-to-breast-cancer-therapy
#9
Gwennaëlle C Monnot, Pedro Romero
Despite great advances in early detection, as well as surgical resection of breast tumours, breast cancer remains the deadliest cancer for women worldwide. Moreover, its incidence is without pair, accounting for twice as many new cancer cases as the second most prevalent cancer, colorectal carcinoma. There is therefore a strong need for new therapeutic approaches to breast cancers. Immunotherapies are novel treatment modalities which aim to use immune mediators to attack cancerous cells. Recent clinical results show that these may not only mediate tumour regressions but also cures in some cases...
June 16, 2017: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/28626031/mismatch-repair-deficiency-confers-sensitivity-to-checkpoint-blockade
#10
(no author information available yet)
PD-1 blockade with pembrolizumab achieves responses in 53% of patients with MMR-deficient tumors.
June 16, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28623775/cancer-immunotherapy-opportunities-and-challenges-in-the-rapidly-evolving-clinical-landscape
#11
REVIEW
Leisha A Emens, Paolo A Ascierto, Phillip K Darcy, Sandra Demaria, Alexander M M Eggermont, William L Redmond, Barbara Seliger, Francesco M Marincola
Cancer immunotherapy is now established as a powerful way to treat cancer. The recent clinical success of immune checkpoint blockade (antagonists of CTLA-4, PD-1 and PD-L1) highlights both the universal power of treating the immune system across tumour types and the unique features of cancer immunotherapy. Immune-related adverse events, atypical clinical response patterns, durable responses, and clear overall survival benefit distinguish cancer immunotherapy from cytotoxic cancer therapy. Combination immunotherapies that transform non-responders to responders are under rapid development...
June 14, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28621843/metabolic-reprogramming-in-the-tumour-microenvironment-a-hallmark-shared-by-cancer-cells-and-t-lymphocytes
#12
REVIEW
Katrina E Allison, Brenda L Coomber, Byram W Bridle
Altered metabolism is a hallmark of cancers, including shifting oxidative phosphorylation to glycolysis and upregulating glutaminolysis to divert carbon sources into biosynthetic pathways that promote proliferation and survival. Therefore, metabolic inhibitors represent promising anti-cancer drugs. However, T cells must rapidly divide and survive in harsh microenvironments to mediate anti-cancer effects. Metabolic profiles of cancer cells and activated T lymphocytes are similar, raising the risk of metabolic inhibitors impairing the immune system...
June 16, 2017: Immunology
https://www.readbyqxmd.com/read/28621686/pseudoprogression-in-microsatellite-instability-high-colorectal-cancer-during-treatment-with-combination-t-cell-mediated-immunotherapy-a-case-report-and-literature-review
#13
Young Kwang Chae, Si Wang, Halla Nimeiri, Aparna Kalyan, Francis J Giles
Evading tumor-mediated immunosuppression through antibodies to immune checkpoints has shown clinical benefit in patients with select solid tumors. There is a heterogeneity of responses in patients receiving immunotherapy, including pseudoprogression in which the tumor burden increases initially before decreasing to reach disease control. The characteristics and basis of pseudoprogression, however, remains poorly understood. We hereby report a case of microsatellite instability (MSI)-high metastatic colorectal cancer treated with combination of OX40 agonist and programmed death ligand-1 (PD-L1) antagonist that demonstrated pseudoprogression reaching 163% increase from baseline tumor burden...
June 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28619999/pd-l2-expression-in-human-tumors-relevance-to-anti-pd-1-therapy-in-cancer
#14
Jennifer H Yearley, Christopher Gibson, Ni Yu, Christina Moon, Erin Murphy, Jonathan Juco, Jared Lunceford, Jonathan Cheng, Laura Q M Chow, Tanguy Y Seiwert, Masahisa Handa, Joanne E Tomassini, Terrill McClanahan
Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1-directed immunotherapy. However, PD-L1-negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay...
June 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28619747/successful-immune-checkpoint-blockade-in-a-patient-with-advanced-stage-microsatellite-unstable-biliary-tract-cancer
#15
Elena Czink, Matthias Kloor, Benjamin Goeppert, Stefan Froehling, Sebastian Uhrig, Tim F Weber, Joern Meinel, Christian Sutter, Karl Heinz Weiss, Peter Schirmacher, Magnus von Knebel Doeberitz, Dirk Jaeger, Christoph Springfeld
Cancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and re-activate anti-tumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/PD-L1 pathway have shown clinical efficacy...
June 15, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28615538/expression-of-lag-3-defines-exhaustion-of-intratumoral-pd-1-t-cells-and-correlates-with-poor-outcome-in-follicular-lymphoma
#16
Zhi-Zhang Yang, Hyo Jin Kim, Jose C Villasboas, Ya-Ping Chen, Tammy Price-Troska, Shahrzad Jalali, Mara Wilson, Anne J Novak, Stephen M Ansell
Exhausted T-cells in follicular lymphoma (FL) typically express PD-1, but expression of PD-1 is not limited to exhausted cells. Although expected to be functionally suppressed, we found that the population of intratumoral PD-1+ T cells were predominantly responsible for production of cytokines and granules. This surprising finding prompted us to explore the involvement of LAG-3 to specifically identify functionally exhausted T cells. We found that LAG-3 was expressed on a subset of intratumoral T cells from FL and LAG-3+ T cells almost exclusively came from PD-1+ population...
May 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28615369/clinical-development-of-pd-1-pd-l1-immunotherapy-for-gastrointestinal-cancers-facts-and-hopes
#17
Ian Chau
Gastrointestinal (GI) cancers are among the most deadly malignancies. Whereas serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumours of each primary anatomical site, it also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success...
June 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28613923/the-era-of-checkpoint-blockade-in-lung-cancer-taking-the-brakes-off-the-immune-system
#18
Edmund K Moon, Corey J Langer, Steven M Albelda
Despite recent advances with targeted kinase inhibitors and better tolerated chemotherapy, the treatment of metastatic non-small cell lung cancer (NSCLC) remains suboptimal. One recent advance that holds great promise is immunotherapy - an approach that enhances a patient's immune system to better recognize and react to abnormal cells. The most successful immunotherapeutic strategy to date uses antibodies to block inhibitory receptors (also called "checkpoints") that are upregulated on the T cells that infiltrate the tumor...
June 14, 2017: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/28613862/small-molecule-inhibitors-of-the-programmed-cell-death-1-programmed-death-ligand-1-pd-1-pd-l1-interaction-via-transiently-induced-protein-states-and-dimerization-of-pd-l1
#19
Katarzyna Guzik, Krzysztof M Zak, Przemyslaw Grudnik, Katarzyna Magiera, Bogdan Musielak, Ricarda Törner, Lukasz Skalniak, Alexander Dömling, Grzegorz Dubin, Tad A Holak
Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb...
June 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28612140/a-phase-ii-study-of-ipilimumab-plus-temozolomide-in-patients-with-metastatic-melanoma
#20
Sapna P Patel, Dae Won Kim, Roland L Bassett, Suzanne Cain, Edwina Washington, Wen-Jen Hwu, Kevin B Kim, Nicholas E Papadopoulos, Jade Homsi, Patrick Hwu, Agop Y Bedikian
Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab...
June 13, 2017: Cancer Immunology, Immunotherapy: CII
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