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https://www.readbyqxmd.com/read/28926356/development-of-bell-s-palsy-after-treatment-with-ipilimumab-and-nivolumab-for-metastatic-melanoma-a-case-report
#1
Julia M Zecchini, Sara Kim, Kendra Yum, Philip Friedlander
Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face...
September 18, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28925087/relationship-of-tumor-pd-l1-cd274-expression-with-lower-mortality-in-lung-high-grade-neuroendocrine-tumor
#2
Kentaro Inamura, Yusuke Yokouchi, Maki Kobayashi, Hironori Ninomiya, Rie Sakakibara, Makoto Nishio, Sakae Okumura, Yuichi Ishikawa
Programmed death-ligand 1 (PD-L1) promotes immunosuppression by binding to PD-1 on T lymphocytes. Although tumor PD-L1 expression is a potential predictive marker of clinical response to anti-PD-1/PD-L1 therapy, little is known about its association with clinicopathological features, including prognosis, in high-grade neuroendocrine tumors (HGNETs), including small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC), of the lung. We immunohistochemically examined the membranous of expression of PD-L1 in 115 consecutive surgical cases of lung HGNET (74 SCLC cases and 41 LCNEC cases)...
September 18, 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28923100/checkpoint-inhibitor-is-active-against-large-cell-neuroendocrine-carcinoma-with-high-tumor-mutation-burden
#3
Victoria E Wang, Anatoly Urisman, Lee Albacker, Siraj Ali, Vincent Miller, Rahul Aggarwal, David Jablons
BACKGROUND: Large cell neuroendocrine tumor (LCNEC) of the lung is a rare and aggressive tumor similar to small cell lung cancer (SCLC). Thus, it is often treated similarly to SCLC in the front-line setting with a platinum doublet. However, treatment for patients beyond the first line remains undefined. CASE PRESENTATION: We report the case of a patient with stage IB LCNEC (PD-L1 negative but positive for PD-L1 amplification and tumor mutation burden high) who progressed after adjuvant chemotherapy after surgery and subsequent therapy with an antibody drug conjugate targeting a neuroendocrine-specific cell surface marker but achieved a significant and durable response with pembrolizumab, a humanized IgG4 monoclonal anti-PD-1 antibody...
September 19, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28920006/dosing-immunotherapy-combinations-analysis-of-3-526-patients-for-toxicity-and-response-patterns
#4
Mina Nikanjam, Harsh Patel, Razelle Kurzrock
Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014-2016, ASH/ESMO 2014-2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28916749/checkpoint-blockade-immunotherapy-reshapes-the-high-dimensional-phenotypic-heterogeneity-of-murine-intratumoural-neoantigen-specific-cd8-t-cells
#5
M Fehlings, Y Simoni, H L Penny, E Becht, C Y Loh, M M Gubin, J P Ward, S C Wong, R D Schreiber, E W Newell
The analysis of neoantigen-specific CD8(+) T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8(+) T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28915714/the-efficacy-of-anti-pd-1-pd-l1-therapy-and-its-comparison-with-egfr-tkis-for-advanced-non-small-cell-lung-cancer
#6
REVIEW
Zhixin Sheng, Xu Zhu, Yanhua Sun, Yanxia Zhang
PURPOSE: To better understand the efficacy and safety of anti-PD-1/PD-L1 therapy (atezolizumab, pembrolizumab, nivolumab) in patients with previously treated advanced non-small-cell lung cancer (NSCLC). METHODS: The Cochrane Controlled Trial Register, Embase, Medline, and the Science Citation Index were searched for prospective published reports of atezolizumab, pembrolizumab, nivolumab in previously treated patients with advanced NSCLC. RESULTS: Finally, we identified 14 prospective published reports including four trials of atezolizumab covering 542 subjects, three trials of pembrolizumab covering 1566 subjects, seven trials of nivolumab covering 1678 subjects...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914717/the-relationship-between-mismatch-repair-deficiency-and-pd-l1-expression-in-breast-carcinoma
#7
Anne M Mills, Erik A Dill, Christopher A Moskaluk, Jaroslaw Dziegielewski, Tim N Bullock, Patrick M Dillon
Mismatch repair (MMR) deficiency in solid tumors has recently been linked to susceptibility to immunotherapies targeting the programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) axis. Loss of MMR proteins has been shown to correlate with tumoral PD-L1 expression in colorectal and endometrial carcinomas, but the association between expression of MMR proteins and PD-L1 has not previously been studied in breast carcinoma, where MMR deficiency is less common. We assessed the relationship between PD-L1 and MMR protein expression by immunohistochemistry in 245 primary and 40 metastatic breast carcinomas...
September 13, 2017: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/28914644/systemic-therapy-in-advanced-melanoma-integrating-targeted-therapy-and-immunotherapy-into-clinical-practice
#8
Inês P Silva, Georgina V Long
PURPOSE OF REVIEW: Here we review the results from relevant phase III trials and discuss treatment strategies for challenging subgroups of melanoma patients. RECENT FINDINGS: Targeted therapies induce rapid responses in the majority of BRAF-mutant patients, however, 50% of these responders will develop resistance within approximately 13 months. In contrast, inhibitors of checkpoints on T cells, particularly inhibitors of PD-1, induce responses in 40-55% of patients (monotherapy or whenever combined with anti-CTLA-4), and these responses tend to be durable...
September 12, 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/28913853/dose-rationalisation-of-pembrolizumab-and-nivolumab-using-pharmacokinetic-modelling-and-simulation-and-cost-analysis
#9
Kayode Ogungbenro, Alkesh Patel, Robert Duncombe, Richard Nuttall, James Clark, Paul Lorigan
Pembrolizumab and nivolumab are highly selective anti PD-1 antibodies approved for the treatment of advanced malignancies. Variable exposure and significant wastage have been associated with body size dosing of monoclonal antibodies. The following dosing strategies were evaluated using simulations: body weight, dose banding, fixed dose and pharmacokinetics based method. The relative cost to body weight dosing for band, fixed 150 mg and 200 mg, and pharmacokinetics derived strategies were -15%, -25%, +7% and -16% for pembrolizumab and -8%, -6%, and -10% for band, fixed, and pharmacokinetics derived strategies for nivolumab...
September 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28912897/genomic-analysis-of-tumor-microenvironment-immune-types-across-14-solid-cancer-types-immunotherapeutic-implications
#10
Yu-Pei Chen, Yu Zhang, Jia-Wei Lv, Ying-Qin Li, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Ying Sun, Yan-Ping Mao, Jing-Ping Yun, Na Liu, Jun Ma
We performed a comprehensive immuno-genomic analysis of tumor microenvironment immune types (TMITs), which is classified into four groups based on PD-L1+CD8A or PD-L1+cytolytic activity (CYT) expression, across a broad spectrum of solid tumors in order to help identify patients who will benefit from anti- PD-1/PD-L1 therapy. The mRNA sequencing data from The Cancer Genome Atlas (TCGA) of 14 solid cancer types representing 6,685 tumor samples was analyzed. TMIT was classified only for those tumor types that both PD-L1 and CD8A/CYT could prefict mutation and/or neoantigen number...
2017: Theranostics
https://www.readbyqxmd.com/read/28912396/-immune-checkpoint-inhibitors-for-lung-cancer-with-egfr-mutation
#11
Hidetoshi Hayashi, Tetsuya Mitsudomi
Recent clinical evidence that anti-PD-1/PD-L1 antibody therapy is superior to cytotoxic chemotherapy for patients with non-small cell lung cancer(NSCLC)that expresses PD-L1 has lead to a paradigm shift in treatment strategies for those patients. However, efficacy of anti-PD-1/PD-L1 antibodies for patients with NSCLC harboring EGFR mutation is generally poor. This lack ofresponse is at least partially attributed to suppression oftumor infiltrating lymphocytes caused by EGFR pathway activation or to low non-synonymous mutation load in NSCLC with EGFR mutation...
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28912137/enhanced-cancer-immunotherapy-by-chimeric-antigen-receptor-modified-t-cells-engineered-to-secrete-checkpoint-inhibitors
#12
Pin Wang, Si Li, Natnaree Siriwon, Xiaoyang Zhang, Shuai Yang, Tao Jin, Feng He, Yu Jeong Kim, John Mac, Zhengfei Lu, Sijie Wang, Xiaolu Han
PURPOSE: Despite favorable responses of CAR-engineered T cell therapy in patients with hematologic malignancies, the outcome has been far from satisfactory in the treatment of solid tumors, partially owing to the development of an immunosuppressive tumor microenvironment. To overcome this limitation, we engineered CAR-T cells secreting checkpoint inhibitors (CPIs) targeting PD-1 (CAR.αPD1-T) and evaluated their efficacy in a human lung carcinoma xenograft mouse model. EXPERIMENTAL DESIGN: To evaluate the effector function and expansion capacity of CAR...
September 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28904066/pd-1-status-in-cd8-t-cells-associates-with-survival-and-anti-pd-1-therapeutic-outcomes-in-head-and-neck-cancer
#13
Benjamin A Kansy, Fernando Concha-Benavente, Raghvendra M Srivastava, Hyun-Bae Jie, Gulidanna Shayan, Yu Lei, Jessica Moskovitz, Jennifer Moy, Jing Li, Sven Brandau, Stephan Lang, Nicole C Schmitt, Gordon J Freeman, William E Gooding, David A Clump, Robert L Ferris
Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1(+) TIL has been reported in human papillomavirus (HPV)(+) HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1(high) T cells may be more exhausted than PD-1(low) T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy...
September 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28903456/tumor-reductive-therapies-and-antitumor-immunity
#14
REVIEW
Huiqin Guo, Kangla Tsung
Tumor reductive therapy is to reduce tumor burden through direct killing of tumor cells. So far, there is no report on the connection between antitumor immunity and tumor reductive therapies. In the last few years, a new category of cancer treatment, immunotherapy, emerged and they are categorized separately from classic cytotoxic treatments (chemo and radiation therapy). The most prominent examples include cellular therapies (LAK and CAR-T) and immune checkpoint inhibitors (anti-PD-1 and CTLA-4). Recent advances in clinical immunotherapy and our understanding of the mechanism behind them revealed that these therapies have a closer relationship with classic cancer treatments than we thought...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28886381/oncolytic-virotherapy-promotes-intratumoral-t-cell-infiltration-and-improves-anti-pd-1-immunotherapy
#15
Antoni Ribas, Reinhard Dummer, Igor Puzanov, Ari VanderWalde, Robert H I Andtbacka, Olivier Michielin, Anthony J Olszanski, Josep Malvehy, Jonathan Cebon, Eugenio Fernandez, John M Kirkwood, Thomas F Gajewski, Lisa Chen, Kevin S Gorski, Abraham A Anderson, Scott J Diede, Michael E Lassman, Jennifer Gansert, F Stephen Hodi, Georgina V Long
Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria...
September 7, 2017: Cell
https://www.readbyqxmd.com/read/28886380/nf-%C3%AE%C2%BAb-c-rel-is-crucial-for-the-regulatory-t-cell-immune-checkpoint-in-cancer
#16
Yenkel Grinberg-Bleyer, Hyunju Oh, Alexis Desrichard, Dev M Bhatt, Rachel Caron, Timothy A Chan, Roland M Schmid, Ulf Klein, Matthew S Hayden, Sankar Ghosh
Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors...
September 7, 2017: Cell
https://www.readbyqxmd.com/read/28886376/converting-cold-into-hot-tumors-by-combining-immunotherapies
#17
John B A G Haanen
In a small phase Ib study in this issue of Cell, Ribas et al. report that the combination of intralesional injection of a modified human herpes simplex virus and systemic anti-PD-1 treatment resulted in a 62% response rate in patients with metastatic melanoma, accompanied by enhanced T cell infiltration in virus-injected lesions.
September 7, 2017: Cell
https://www.readbyqxmd.com/read/28883282/development-of-immune-checkpoint-inhibitors
#18
Shigehisa Kitano
Immune checkpoint inhibitors are the most striking innovation in the clinical development of immunotherapy. Monoclonal antibodies (mAbs) restore and augment the antitumor immune activities of cytotoxic T cells by mainly blocking immune checkpoint molecules on T cells or their ligands on antigen-presenting and tumor cells. Based on preclinical data, many clinical trials have demonstrated the acceptable safety profiles and efficacies of mAb in various cancers. The A first-in-class approved immune checkpoint inhibitor is ipilimumab, which is a fully humanized mAb that blocks the immunosuppressive signal by cytotoxic T-lymphocyte antigen 4...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28881780/pd-l1-a-novel-prognostic-biomarker-in-head-and-neck-squamous-cell-carcinoma
#19
Tim Müller, Martin Braun, Dimo Dietrich, Seher Aktekin, Simon Höft, Glen Kristiansen, Friederike Göke, Andreas Schröck, Johannes Brägelmann, Stefanie A E Held, Friedrich Bootz, Peter Brossart
BACKGROUND: The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical trials against several tumor entities with promising results. However, until now comprehensive data with regard to PD-L1 and PD-L2 expression in head and neck squamous cell carcinoma (HNSCC) is still lacking...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881642/pd-1-and-pd-l1-expression-in-132-recurrent-nasopharyngeal-carcinoma-the-correlation-with-anemia-and-outcomes
#20
Yajuan Zhou, Jingjing Miao, Haijun Wu, Hao Tang, Jing Kuang, Xiaoyi Zhou, Yi Peng, Desheng Hu, Dingbo Shi, Wuguo Deng, Xinyue Cao, Chong Zhao, Conghua Xie
The expression of Programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) has been reported to be reliable prognostic factors in various malignances including primary nasopharyngeal carcinoma (NPC). However, the exact role of PD-1/PD-L1 in recurrent NPC remains unclear. In this study, we aimed to investigate the relationship between the expression of PD-1 / PD-L1 and the clinical-pathology as well the outcomes of recurrent NPC patients (n = 132). The expression of PD-1 and PD-L1 was measured by immunohistochemistry staining...
August 1, 2017: Oncotarget
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