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Cancer and immune checkpoint

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https://www.readbyqxmd.com/read/29473504/immunotherapy-in-non-small-cell-lung-cancer-biological-principles-and-future-opportunities
#1
M Ilie, J Benzaquen, V Hofman, S Lassalle, N Yazbeck, S Leroy, S Heeke, C Bence, B Mograbi, N Glaichenhaus, C H Marquette, P Hofman
Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC)...
February 21, 2018: Current Molecular Medicine
https://www.readbyqxmd.com/read/29473428/a-patent-review-of-ido1-inhibitors-for-cancer
#2
Jae Eun Cheong, Anil Ekkati, Lijun Sun
Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials. Areas covered: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively...
February 23, 2018: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/29473249/immune-checkpoint-inhibitors-in-cancer-therapy-a-focus-on-t-regulatory-cells-by-varun-sasidharan-nair-and-eyad-elkord-erratum
#3
(no author information available yet)
No abstract text is available yet for this article.
February 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29472156/novel-biomarkers-in-bladder-cancer
#4
REVIEW
Michael L Cheng, Gopa Iyer
A sea change has occurred in the treatment options available for metastatic urothelial bladder cancer with the recent Food and Drug Administration approval of 5 immune checkpoint blockade agents for patients who have progressed on platinum-based chemotherapy or are not candidates for cisplatin. Additionally, comprehensive characterization of the landscape of genomic alterations in this disease through The Cancer Genome Atlas and other efforts has detected numerous potential targets for small molecule inhibitors...
February 19, 2018: Urologic Oncology
https://www.readbyqxmd.com/read/29471699/atezolizumab-for-the-treatment-of-colorectal-cancer-the-latest-evidence-and-clinical-potential
#5
Gonzalo Tapia Rico, Timothy J Price
Atezolizumab is a fully humanized, engineered monoclonal antibody (MAb) of IgG1 isotype that specifically targets programmed death ligand 1 (PD-L1), a key molecule in the cancer-immunity pathway. Atezolizumab is currently approved for the treatment of metastatic non-small-cell lung cancer (NSCLC) and advanced urothelial carcinomas. Areas covered: In this review, we will present the available (early phase clinical trials) data supporting the efficacy of atezolizumab for the treatment of metastatic colorectal cancer (mCRC)...
February 23, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29471676/results-and-challenges-of-immune-checkpoint-inhibitors-in-colorectal-cancer
#6
Sheik Emambux, Gaelle Tachon, Audelaure Junca, David Tougeron
Introduction Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8+ T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8+ T cells to a state of anergy...
February 22, 2018: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/29470785/the-abscopal-effect-in-the-era-of-cancer-immunotherapy-a-spontaneous-synergism-boosting-anti-tumor-immunity
#7
Zuzana Hlavata, Cinzia Solinas, Pushpamali De Silva, Michele Porcu, Luca Saba, Karen Willard-Gallo, Mario Scartozzi
Radiotherapy is one of the main treatment strategies used in cancer. Aside from the local control of the disease, which is mediated by a direct cytotoxic effect on tumor cells, radiotherapy has also been shown to exert immune-mediated local and systemic effects. Radiotherapy can elicit anti-tumor responses in distant sites from the radiation field; this phenomenon is known as the abscopal effect and has been described in patients previously treated with immune checkpoint blockade (ICB). Considering that the efficacy of immunotherapy has been demonstrated only in a subset of patients-who often benefit with lasting responses-efforts are ongoing to potentiate its activity with the development of new combination strategies...
February 22, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29470579/defining-the-most-appropriate-primary-end-point-in-phase-2-trials-of-immune-checkpoint-inhibitors-for-advanced-solid-cancers-a-systematic-review-and-meta-analysis
#8
Georgia Ritchie, Harry Gasper, Johnathan Man, Sally Lord, Ian Marschner, Michael Friedlander, Chee Khoon Lee
Importance: Checkpoint inhibitors have a unique mechanism of action that differs from chemotherapy or targeted therapies. The validity of objective response rate (ORR) as a surrogate for progression-free survival (PFS) and overall survival (OS) in checkpoint-inhibitor trials is uncertain. Objective: To determine the types of primary end points used in phase 2 checkpoint-inhibitor trials, and to assess the strength of associations for ORR with PFS and OS. Data Sources: Trials listed in electronic databases from 2000 to 2017 (PREMEDLINE, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials)...
February 22, 2018: JAMA Oncology
https://www.readbyqxmd.com/read/29469949/safety-profile-of-avelumab-in-patients-with-advanced-solid-tumors-a-pooled-analysis-of-data-from-the-phase-1-javelin-solid-tumor-and-phase-2-javelin-merkel-200-clinical-trials
#9
Karen Kelly, Jeffrey R Infante, Matthew H Taylor, Manish R Patel, Deborah J Wong, Nicholas Iannotti, Janice M Mehnert, Anja H Loos, Helga Koch, Isabell Speit, James L Gulley
BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks...
February 22, 2018: Cancer
https://www.readbyqxmd.com/read/29467463/bifunctional-immune-checkpoint-targeted-antibody-ligand-traps-that-simultaneously-disable-tgf%C3%AE-enhance-the-efficacy-of-cancer-immunotherapy
#10
Rajani Ravi, Kimberly A Noonan, Vui Pham, Rishi Bedi, Alex Zhavoronkov, Ivan V Ozerov, Eugene Makarev, Artem V Artemov, Piotr T Wysocki, Ranee Mehra, Sridhar Nimmagadda, Luigi Marchionni, David Sidransky, Ivan M Borrello, Evgeny Izumchenko, Atul Bedi
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH 1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd)...
February 21, 2018: Nature Communications
https://www.readbyqxmd.com/read/29467274/jak2-inhibitor-sar302503-abrogates-pd-l1-expression-and-targets-therapy-resistant-non-small-cell-lung-cancers
#11
Sean Pitroda, Melinda Stack, Gene-Fu Liu, Sui-Sui Song, Lucy Chen, Hua Liang, Akash D Parekh, Xiaona Huang, Paul B Roach, Mitchell C Posner, Ralph R Weichselbaum, Nikolai N Khodarev
Lung cancer is the leading cause of cancer deaths worldwide. Approximately 85% of all lung cancers are non-small-cell histology (NSCLC). Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than fifteen percent of patients survive beyond five years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide...
February 21, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29464975/pembrolizumab-and-its-use-in-the-treatment-of-recurrent-or-metastatic-head-and-neck-cancer
#12
Siddharth Sheth, Jared Weiss
Until recently, palliative options for the treatment of platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have been cytotoxic chemotherapy and EGFR inhibitors. These agents offer limited efficacy with substantial toxicity. The development of novel immune checkpoint inhibitors has challenged the standard treatment. Pembrolizumab is a potent and highly selective humanized monoclonal antibody that blocks the interaction between PD-1, an immune checkpoint receptor and its ligands PD-L1 and -2...
February 21, 2018: Future Oncology
https://www.readbyqxmd.com/read/29464699/immune-checkpoint-blockade-combined-with-il-6-and-tgf-%C3%AE-inhibition-improves-the-therapeutic-outcome-of-mrna-based-immunotherapy
#13
Lukasz Bialkowski, Kevin Van der Jeught, Sanne Bevers, Patrick Tjok Joe, Dries Renmans, Carlo Heirman, Joeri L Aerts, Kris Thielemans
Improved understanding of cancer immunology has provided insight into the phenomenon of frequent tumor recurrence after initially successful immunotherapy. A delicate balance exists between the capacity of the immune system to control tumor growth and various resistance mechanisms that arise to avoid or even counteract the host's immune system. These resistance mechanisms include, but are not limited to (1) adaptive expression of inhibitory checkpoint molecules in response to the pro-inflammatory environment and (2) amplification of cancer stem cells, a small fraction of tumor cells possessing the capacity for self-renewal and mediating treatment resistance and formation of metastases after long periods of clinical remission...
February 21, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29464405/the-role-of-circulating-tumor-dna-in-renal-cell-carcinoma
#14
REVIEW
Paulo G Bergerot, Andrew W Hahn, Cristiane Decat Bergerot, Jeremy Jones, Sumanta Kumar Pal
Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a novel technology that can complement tumor tissue NGS and has the potential to influence diagnosis and treatment of both localized and metastatic renal cell carcinoma (mRCC). ctDNA NGS is an attractive alternative to tumor tissue NGS because it circumvents the need for repeated, invasive tissue biopsies while providing a contemporary mutational profile of a patient's tumors. While the role of ctDNA NGS in non-small cell lung cancer and colorectal cancer is well established, studies of ctDNA NGS in mRCC are only hypothesis-generating to date...
February 20, 2018: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/29464067/gene-aberration-profile-of-tumors-of-adolescent-and-young-adult-females
#15
Yasuyuki Kanke, Akihiko Shimomura, Motonobu Saito, Takayuki Honda, Kouya Shiraishi, Yoko Shimada, Reiko Watanabe, Hiroshi Yoshida, Masayuki Yoshida, Chikako Shimizu, Kazuaki Takahashi, Hirohiko Totsuka, Hideaki Ogiwara, Sou Hirose, Koji Kono, Kenji Tamura, Aikou Okamoto, Takayuki Kinoshita, Tomoyasu Kato, Takashi Kohno
There has been little improvement in the prognosis for adolescent and young adult (AYA) tumor patients. Hence, there is an urgent need to understand the etiology of tumor development and identify actionable gene aberrations to improve prevention and therapy. Here, 76 sporadic tumors (48 breast, 22 ovarian, and six uterine) from 76 AYA females (age range, 25-39 years) were subjected to whole exome and RNA sequencing to determine their mutational signatures and actionable gene profiles. Two individuals with breast cancer (4...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29464065/the-presence-of-pd-1-positive-tumor-infiltrating-lymphocytes-in-triple-negative-breast-cancers-is-associated-with-a-favorable-outcome-of-disease
#16
Gero Brockhoff, Stephan Seitz, Florian Weber, Florian Zeman, Monika Klinkhammer-Schalke, Olaf Ortmann, Anja Kathrin Wege
Triple negative breast cancer patients have a poor course of disease not least because of limited treatment options however immunotherapy by targeting the PD-1/PD-L1 checkpoint system is a promising strategy to improve the outcome. Here we systematically investigated the expression of PD-1 on tumor infiltrating lymphocytes and PD-L1 on both tumor and infiltrated immune cells. Moreover, the PD-L1 gene status in tumor cells was assessed. 103 tissue microarray samples derived from triple negative breast cancer specimens were immunohistochemically stained against PD-1 and PD-L1...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29464025/microsatellite-instability-is-a-biomarker-for-immune-checkpoint-inhibitors-in-endometrial-cancer
#17
Hitomi Yamashita, Kentaro Nakayama, Masako Ishikawa, Kohei Nakamura, Tomoka Ishibashi, Kaori Sanuki, Ruriko Ono, Hiroki Sasamori, Toshiko Minamoto, Kouji Iida, Razia Sultana, Noriyoshi Ishikawa, Satoru Kyo
In recent years, it has become evident that tumor cells have immune escape mechanisms, and immune checkpoint inhibitor therapy (anti-PD-1/PD-L1 antibody) has shown benefit in various cancers. In endometrial tumors with microsatellite-instability (MSI), somatic mutations have the potential to encode ''non-self'' immunogenic antigens, and lymphocytes have been shown to infiltrate the tumor. Therefore, immune checkpoint inhibitor therapy might be effective in endometrial cancers with MSI. Expression of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), the presence of tumor-infiltrating lymphocytes (CD8+), and PD-1/PD-L1 expression were assessed by immunohistochemistry in 149 patients with endometrial cancer...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29463044/the-role-of-the-estrogen-pathway-in-the-tumor-microenvironment
#18
REVIEW
Natalie J Rothenberger, Ashwin Somasundaram, Laura P Stabile
Estrogen receptors are broadly expressed in many cell types involved in the innate and adaptive immune responses, and differentially regulate the production of cytokines. While both genomic and non-genomic tumor cell promoting mechanisms of estrogen signaling are well characterized in multiple carcinomas including breast, ovarian, and lung, recent investigations have identified a potential immune regulatory role of estrogens in the tumor microenvironment. Tumor immune tolerance is a well-established mediator of oncogenesis, with increasing evidence indicating the importance of the immune response in tumor progression...
February 19, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29462255/osimertinib-and-other-third-generation-egfr-tki-in-egfr-mutant-nsclc-patients
#19
J Remon, C E Steuer, S S Ramalingam, E Felip
Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29462132/development-of-a-prognostic-scoring-system-for-patients-with-advanced-cancer-enrolled-in-immune-checkpoint-inhibitor-phase-1-clinical-trials
#20
Shiraj Sen, Kenneth Hess, David S Hong, Aung Naing, Sarina Piha-Paul, Filip Janku, Siqing Fu, Ishwaria M Subbiah, Holly Liu, Rahil Khanji, Le Huang, Shhyam Moorthy, Daniel D Karp, Apostolia Tsimberidou, Funda Meric-Bernstam, Vivek Subbiah
BACKGROUND: We sought to develop a prognostic scoring system to aid in patient selection for immune checkpoint inhibitor (ICI) phase 1 clinical trials. METHODS: Clinical data from patients treated in phase 1 ICI clinical trials at MD Anderson (MDA) Center were analysed. Seventeen clinical factors were studied. Recursive partitioning analysis, a tree-based model, was used to develop a regression tree and identify optimal cut-points based on differences in survival for each clinical factor...
February 20, 2018: British Journal of Cancer
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