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https://www.readbyqxmd.com/read/29349763/immune-checkpoint-blockade-for-breast-cancer
#1
April Swoboda, Rita Nanda
An effective antitumor immune response requires interaction between cells of the adaptive and innate immune system. Three key elements are required: generation of activated tumor-directed T cells, infiltration of activated T cells into the tumor microenvironment, and killing of tumor cells by activated T cells. Tumor immune evasion can occur as a result of the disruption of each of these three key T cell activities, resulting in three distinct cancer-immune phenotypes. The immune inflamed phenotype, characterized by the presence of a robust tumor immune infiltrate, suggests impaired activated T cell killing of tumor cells related to the presence of inhibitory factors...
2018: Cancer Treatment and Research
https://www.readbyqxmd.com/read/29343622/enhanced-preclinical-antitumor-activity-of-m7824-a-bifunctional-fusion-protein-simultaneously-targeting-pd-l1-and-tgf-%C3%AE
#2
Yan Lan, Dong Zhang, Chunxiao Xu, Kenneth W Hance, Bo Marelli, Jin Qi, Huakui Yu, Guozhong Qin, Aroop Sircar, Vivian M Hernández, Molly H Jenkins, Rachel E Fontana, Amit Deshpande, George Locke, Helen Sabzevari, Laszlo Radvanyi, Kin-Ming Lo
Antibodies targeting immune checkpoints are emerging as potent and viable cancer therapies, but not all patients respond to these as single agents. Concurrently targeting additional immunosuppressive pathways is a promising approach to enhance immune checkpoint blockade, and bifunctional molecules designed to target two pathways simultaneously may provide a strategic advantage over the combination of two single agents. M7824 (MSB0011359C) is a bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the extracellular domain of human transforming growth factor-β (TGF-β) receptor II, which functions as a "trap" for all three TGF-β isoforms...
January 17, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29339440/repurposing-tin-mesoporphyrin-as-an-immune-checkpoint-inhibitor-shows-therapeutic-efficacy-in-preclinical-models-of-cancer
#3
Tamara Muliaditan, James W Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F Madden, Joy M Burchell, Shahram Kordasti, Sandra S Diebold, James Spicer, James N Arnold
PURPOSE: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immune suppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited anti-tumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinaemia, as an immune checkpoint blockade therapy for the treatment of cancer...
January 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29339377/robust-antitumor-responses-result-from-local-chemotherapy-and-ctla-4-blockade
#4
Charlotte E Ariyan, Mary Sue Brady, Robert H Siegelbaum, Jian Hu, Danielle M Bello, Jamie Green, Charles Fisher, Robert A Lefkowitz, Katherine S Panageas, Melissa Pulitzer, Marissa Vignali, Ryan Emerson, Christopher Tipton, Harlan Robins, Taha Merghoub, Jianda Yuan, Achim Jungbluth, Jorge Blando, Padmanee Sharma, Alexander Y Rudensky, Jedd D Wolchok, James P Allison
Clinical responses to immunotherapy have been associated with augmentation of preexisting immune responses, manifested by heightened inflammation in the tumor microenvironment. However, many tumors have a non-inflamed microenvironment, and response rates to immunotherapy in melanoma have been <50%. We approached this problem by utilizing immunotherapy (CTLA-4 blockade) combined with chemotherapy to induce local inflammation. In murine models of melanoma and prostate cancer, the combination of chemotherapy and CTLA-4 blockade induced a shift in the cellular composition of the tumor microenvironment, with infiltrating CD8+ and CD4+ T cells increasing the CD8/Foxp3 T-cell ratio...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29339375/tusc2-immunogene-synergizes-with-anti-pd1-through-enhanced-proliferation-and-infiltration-of-natural-killer-cells-in-syngeneic-kras-mutant-mouse-lung-cancer-models
#5
Ismail M Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veerabhadran Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji, Jack A Roth
Expression of the multikinase inhibitor encoded by tumor suppressor gene TUSC2 (also known as FUS1) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras-mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29339209/extratumoral-pd-1-blockade-does-not-perpetuate-obesity-associated-inflammation-in-esophageal-adenocarcinoma
#6
Karen C Galvin, Melissa J Conroy, Suzanne L Doyle, Margaret R Dunne, Ronan Fahey, Emma Foley, Katie E O'Sullivan, Derek G Doherty, Justin G Geoghegan, Narayanasamy Ravi, Cliona O'Farrelly, John V Reynolds, Joanne Lysaght
Checkpoint inhibitors, such as anti-PD-1 (Programmed death-1), are transforming cancer treatment for inoperable or advanced disease. As the incidence of obesity-associated malignancies, including esophageal adenocarcinoma (EAC) continue to increase and treatment with checkpoint inhibitors are being FDA approved for a broader range of cancers, it is important to assess how anti-PD-1 treatment might exacerbate pre-existing inflammatory processes at other sites. Outside the EAC tumor, the omentum and liver were found to be enriched with substantial populations of PD-1 expressing T cells...
January 12, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29338610/cns-side-effects-of-immune-checkpoint-inhibitors-preclinical-models-genetics-and-multimodality-therapy
#7
Gwendolyn J McGinnis, Jacob Raber
Following cancer treatment, patients often report behavioral and cognitive changes. Novel cancer immunotherapeutics have the potential to produce sustained cancer survivorship, meaning patients will live longer with the side effects of treatment. Given the role of inflammatory pathways in mediating behavioral and cognitive impairments seen in cancer, we aim in this review to discuss emerging evidence for the contribution of immune checkpoint blockade to exacerbate these CNS effects. We discuss ongoing studies regarding the ability of immune checkpoint inhibitors to reach the brain and how treatment responses to checkpoint inhibitors may be modulated by genetic factors...
September 2017: Immunotherapy
https://www.readbyqxmd.com/read/29338609/chemotherapy-induced-immunomodulation-in-non-small-cell-lung-cancer-a-rationale-for-combination-chemoimmunotherapy
#8
Hua Zheng, Masha Zeltsman, Marjorie G Zauderer, Takashi Eguchi, Raj G Vaghjiani, Prasad S Adusumilli
Spurred by the survival benefits seen with the use of checkpoint blockade in non-small-cell lung cancer (NSCLC), there has been a growing interest in the potential applications of immunotherapy. Despite this, the objective response rate for single-agent immunotherapy remains ≤20% in patients with advanced NSCLC. A combinatorial approach that utilizes both chemotherapy and immunotherapy is a potential strategy to increase antitumor efficacy. Accumulating evidence has shown that the immunomodulatory effects of chemotherapeutic agents can be exploited in a combinational approach...
September 2017: Immunotherapy
https://www.readbyqxmd.com/read/29337640/molecular-determinants-of-response-to-anti-programmed-cell-death-pd-1-and-anti-programmed-death-ligand-pd-l-ligand-1-blockade-in-patients-with-non-small-cell-lung-cancer-profiled-with-targeted-next-generation-sequencing
#9
Hira Rizvi, Francisco Sanchez-Vega, Konnor La, Walid Chatila, Philip Jonsson, Darragh Halpenny, Andrew Plodkowski, Niamh Long, Jennifer L Sauter, Natasha Rekhtman, Travis Hollmann, Kurt A Schalper, Justin F Gainor, Ronglai Shen, Ai Ni, Kathryn C Arbour, Taha Merghoub, Jedd Wolchok, Alexandra Snyder, Jamie E Chaft, Mark G Kris, Charles M Rudin, Nicholas D Socci, Michael F Berger, Barry S Taylor, Ahmet Zehir, David B Solit, Maria E Arcila, Marc Ladanyi, Gregory J Riely, Nikolaus Schultz, Matthew D Hellmann
Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240)...
January 16, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29337311/dinaciclib-induces-immunogenic-cell-death-and-enhances-anti-pd-1-mediated-tumor-suppression
#10
Dewan Md Sakib Hossain, Sarah Javaid, Mingmei Cai, Chunsheng Zhang, Anandi Sawant, Marlene Hinton, Manjiri Sathe, Jeff Grein, Wendy Blumenschein, Elaine M Pinheiro, Alissa Chackerian
Blockade of the checkpoint inhibitor programmed death 1 (PD1) has demonstrated remarkable success in the clinic for the treatment of cancer; however, a majority of tumors are resistant to anti-PD1 monotherapy. Numerous ongoing clinical combination therapy studies will likely reveal additional therapeutics that complement anti-PD1 blockade. Recent studies found that immunogenic cell death (ICD) improves T cell responses against different tumors, thus indicating that ICD may further augment antitumor immunity elicited by anti-PD1...
January 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29337303/pd-l1-on-host-cells-is-essential-for-pd-l1-blockade-mediated-tumor-regression
#11
Haidong Tang, Yong Liang, Robert A Anders, Janis M Taube, Xiangyan Qiu, Aditi Mulgaonkar, Xin Liu, Susan M Harrington, Jingya Guo, Yangchun Xin, Yahong Xiong, Kien Nham, William Silvers, Guiyang Hao, Xiankai Sun, Mingyi Chen, Raquibul Hannan, Jian Qiao, Haidong Dong, Hua Peng, Yang-Xin Fu
Programmed death-ligand 1 (PD-L1) expression on tumor cells is essential for T cell impairment, and PD-L1 blockade therapy has shown unprecedented durable responses in several clinical studies. Although higher expression of PD-L1 on tumor cells is associated with a better immune response after Ab blockade, some PD-L1-negative patients also respond to this therapy. In the current study, we explored whether PD-L1 on tumor or host cells was essential for anti-PD-L1-mediated therapy in 2 different murine tumor models...
January 16, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29336991/sirp%C3%AE-cd47-immune-checkpoint-blockade-in-anticancer-therapy
#12
REVIEW
André Veillette, Jun Chen
Inhibitory immune checkpoint blockade has been one of the most significant advances in anticancer therapy of the past decade. Research so far has largely focused on improving adaptive immune functions, but recent studies have indicated that the signal-regulatory protein (SIRP)α-CD47 pathway, a phagocytosis checkpoint in macrophages and other innate immune cells, may be an interesting therapeutic target. Here, we summarize current knowledge about SIRPα-CD47 blockade, and highlight key issues for future investigations...
January 11, 2018: Trends in Immunology
https://www.readbyqxmd.com/read/29336307/activation-of-g-protein-coupled-estrogen-receptor-signaling-inhibits-melanoma-and-improves-response-to-immune-checkpoint-blockade
#13
Christopher A Natale, Jinyang Li, Junqian Zhang, Ankit Dahal, Tzvete Dentchev, Ben Z Stanger, Todd W Ridky
Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc...
January 16, 2018: ELife
https://www.readbyqxmd.com/read/29333023/nivolumab-pearls-of-evidence
#14
REVIEW
Pratishtha B Chaudhari
Purpose: Nivolumab is one of the most extensively studied immune checkpoint inhibitors across various tumor types. In this narrative review, the current clinical efficacy and safety data of anti-programmed death-1 (PD-1) nivolumab for nonsmall cell lung cancer (NSCLC) and renal cell cancer (RCC) are elucidated. Methods: Systematic search was done on Pubmed, Medline, Embase, Web of Knowledge, and Cochrane Central through September 2016 for controlled prospective interventional studies of nivolumab across two indications - NSCLC and RCC...
October 2017: Indian Journal of Medical and Paediatric Oncology
https://www.readbyqxmd.com/read/29330759/-autoimmune-reactions-to-immune-checkpoint-inhibitors
#15
REVIEW
W Pönisch, R Alten, C Baerwald
Immune checkpoint inhibitors (ICI) have dramatically changed the face of cancer treatment and are gaining in importance. The ICIs have now been approved for the treatment of advanced cancers, including melanoma, non-small-cell and small cell lung cancers, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancers and urothelial carcinoma and further indications are to be expected. The organs most affected by an autoimmune reaction are the intestines, the musculoskeletal system, skin, endocrine organs, the liver and the lungs...
October 2017: Zeitschrift Für Rheumatologie
https://www.readbyqxmd.com/read/29330552/dosimetry-prediction-for-clinical-translation-of-64cu-pembrolizumab-immunopet-targeting-human-pd-1-expression
#16
Arutselvan Natarajan, Chirag B Patel, Frezghi Habte, Sanjiv S Gambhir
The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64Cu-pembrolizumab radiotracer and evaluated human dosimetry...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29326431/impact-of-oncogenic-pathways-on-evasion-of-antitumour-immune-responses
#17
REVIEW
Stefani Spranger, Thomas F Gajewski
Immunotherapeutic interventions are showing effectiveness across a wide range of cancer types, but only a subset of patients shows clinical response to therapy. Responsiveness to checkpoint blockade immunotherapy is favoured by the presence of a local, CD8+ T cell-based immune response within the tumour microenvironment. As molecular analyses of tumours containing or lacking a productive CD8+ T cell infiltrate are being pursued, increasing evidence is indicating that activation of oncogenic pathways in tumour cells can impair induction or execution of a local antitumour immune response...
January 12, 2018: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/29326088/age-effects-of-distinct-immune-checkpoint-blockade-treatments-in-a-mouse-melanoma-model
#18
Álvaro Padrón, Vincent Hurez, Harshita B Gupta, Curtis A Clark, Sri Lakshmi Pandeswara, Bin Yuan, Robert S Svatek, Mary Jo Turk, Justin M Drerup, Rong Li, Tyler J Curiel
Cancer immunotherapy has shown remarkable recent progress. Immune checkpoint blocking antibodies have become the most successful anti-cancer agent class ever developed, with six distinct agents approved since 2011 for a wide variety of cancers. Although age is the biggest risk factor for cancer (aside from selected early-onset pediatric cancers), these agents were tested pre-clinically in young hosts, and there is remarkably little published on the effects of host age on treatment outcomes in pre-clinical studies or human clinical trials...
January 8, 2018: Experimental Gerontology
https://www.readbyqxmd.com/read/29325739/anti-programmed-cell-death-1-ligand-1-pd-1-pd-l1-antibodies-for-the-treatment-of-urothelial-carcinoma-state-of-the-art-and-future-development
#19
REVIEW
Thomas Powles, Andrea Necchi, Galit Rosen, Subramanian Hariharan, Andrea B Apolo
Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has expanded a previously limited pool of effective treatment options for patients with metastatic urothelial carcinoma, particularly those with recurring or refractory disease and those who are ineligible for cisplatin. This review reports key findings from completed and ongoing clinical trials that highlight the potential of PD-1/PD-L1 blockade in urothelial carcinoma. A literature search was performed of PubMed, Embase, ClinicalTrials...
December 6, 2017: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/29320654/immune-related-adverse-events-associated-with-immune-checkpoint-blockade
#20
Michael A Postow, Robert Sidlow, Matthew D Hellmann
New England Journal of Medicine, Volume 378, Issue 2, Page 158-168, January 2018.
January 11, 2018: New England Journal of Medicine
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