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Checkpoint inhibitors oncology

Steven M Yip, Connor Wells, Raphael Moreira, Alex Wong, Sandy Srinivas, Benoit Beuselinck, Camillo Porta, Hao-Wen Sim, D Scott Ernst, Brian I Rini, Takeshi Yuasa, Naveen S Basappa, Ravindran Kanesvaran, Lori A Wood, Christina Canil, Anil Kapoor, Simon Y F Fu, Toni K Choueiri, Daniel Y C Heng
BACKGROUND: To the authors' knowledge, outcomes and prognostic tools have yet to be clearly defined in patients with metastatic renal cell carcinoma (mRCC) who are treated with immuno-oncology (IO) checkpoint inhibitors (programmed death-ligand 1 [PD-L1] inhibitors). In the current study, the authors aimed to establish IO efficacy benchmarks in patients with mRCC and update patient outcomes in each International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class...
October 11, 2018: Cancer
Ferga C Gleeson, Michael J Levy, Anja C Roden, Lisa A Boardman, Frank A Sinicrope, Robert R McWilliams, Lizhi Zhang
Background and study aims  The US FDA recently approved a cancer treatment with pembrolizumab based upon the tumor biomarker status of deficient mismatch repair (dMMR) rather than a specific disease-based approach. We sought to determine if endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) could determine dMMR and quantification of PD-L1 expression to potentially guide the delivery of tumor agnostic immunotherapy. Patients and methods  Immunohistochemistry was performed on archived pancreas core biopsy specimens...
October 2018: Endoscopy International Open
Jun Gong, Andrew Hendifar, Richard Tuli, Jeremy Chuang, May Cho, Vincent Chung, Daneng Li, Ravi Salgia
Immune checkpoint inhibitors have demonstrated broad single-agent antitumor activity and a favorable safety profile that render them attractive agents to combine with other systemic anticancer therapies. Pancreatic cancer has been fairly resistant to monotherapy blockade of programmed cell death protein 1 receptor, programmed death ligand 1, and cytotoxic T-lymphocyte associated protein 4. However, there is a growing body of preclinical evidence to support the rational combination of checkpoint inhibitors and various systemic therapies in pancreatic cancer...
October 8, 2018: Clinical and Translational Medicine
Hanny Al-Samkari, Gregory D Snyder, Sarah Nikiforow, Sara M Tolaney, Rachel A Freedman, Julie-Aurore Losman
BACKGROUND: Immune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems. OBJECTIVE: Description of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence...
October 4, 2018: Journal of Medical Genetics
C Grávalos, O Sanmartín, A Gúrpide, A España, M Majem, H J Suh Oh, I Aragón, S Segura, C Beato, R Botella
Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1...
October 3, 2018: Clinical & Translational Oncology
Yen Zhi Tang, Bernadett Szabados, Cindy Leung, Anju Sahdev
Immunotherapy has had increasing use in Medical Oncology for a diverse range of primary malignancies. There are various types of immunotherapy which are grouped based on mechanism of action. In recent decades, the immune checkpoint inhibitors (ICI) immunotherapies have been at the forefront of Medical Oncology, sparked by very encouraging results. Some patients with metastatic cancer who were previously deemed palliative were seeing durable response rates and significant increased survival with ICIs. The mechanism of action of ICIs vary wildly compared to the conventional, cytotoxic chemotherapy, upon which traditional radiology response criteria were based and validated upon...
October 16, 2018: British Journal of Radiology
Mauricio Burotto, Juan G Gormaz, Suraj Samtani, Nicolas Valls, Ricardo Silva, Carlos Rojas, Sergio Portiño, Carlos de la Jara
Metastatic cancers during pregnancy have historically been associated with dismal outcomes, with greater rates of tumor progression in part because of diminished treatment alternatives. Immunotherapy with T-cell checkpoint inhibitors has significantly impacted the survival of several metastatic tumors. However, given their mechanism of action, immune-related adverse events can occur, especially with combined immunotherapy treatments. During pregnancy, checkpoint pathways have a major role, providing immune tolerance to the fetal allograft...
March 22, 2018: Seminars in Oncology
Patrick H Lizotte, Ruey-Long Hong, Troy A Luster, Megan E Cavanaugh, Luke J Taus, Stephen Wang, Abha Dhaneshwar, Naomi Mayman, Aaron Yang, Meghana Kulkarni, Lauren Badalucco, Erica Fitzpatrick, Hsiang-Fong Kao, Mari Kuraguchi, Mark Bittinger, Paul T Kirschmeier, Nathanael S Gray, David A Barbie, Pasi A Jänne
We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results...
September 21, 2018: Cancer Immunology Research
Dirk Schadendorf, Alexander C J van Akkooi, Carola Berking, Klaus G Griewank, Ralf Gutzmer, Axel Hauschild, Andreas Stang, Alexander Roesch, Selma Ugurel
Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers...
September 15, 2018: Lancet
Junya Ohtake, Keisuke Kazama, Manabu Shiozawa, Tetsuro Sasada
Colorectal cancer(CRC)is one of the increasing cancers, and development of novel treatments is imperative for advanced CRC. In recent years, immune checkpoint inhibitors have demonstrated impressive clinical efficacy in various types of cancers, but only limited clinical responses were reported in CRC. It has been reported that such poor therapeutic effects might be possibly due to immune suppressive mechanisms other than immune checkpoints in the CRC. Therefore, comprehensive grasp of the immune environment is considered to be of significance for CRC patients...
September 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Yuki Owada-Ozaki, Kyoko Nishiyama, Takahiro Kobayashi, Tatsuo Suzutani, Hiroyuki Suzuki
Currently, anti-PD-1 inhibitors(nivolumab and pembrolizumab)are used for patients with non-small cell lung cancer (NSCLC), although the role of this biomarker is not yet fully characterized. PD-L1 expression in the tumor has been established as a biomarker of the effects of pembrolizumab; however, a number of PD-L1-negative patients have benefited from nivolumab or other immune checkpoint inhibitors, suggesting that there might be additional relevant biomarkers. Notably, tumor mutation burden or tumor infiltrating lymphocytes might be useful biomarkers for these patients; the gut microbiome has received similar attention...
September 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Claudia Dollt, Julia Michel, Loreen Kloss, Susanne Melchers, Kai Schledzewski, Kathrin Becker, Andrea Sauer, Andreas Krewer, Franziska Koll, Astrid Schmieder
Melanoma is a highly immunogenic tumor with a good response to treatment with immune checkpoint inhibitors. Tumor-associated macrophages (TAMs) play an important immunosuppressive role in such tumors and have therefore been identified as possible future therapeutic targets in oncology. The aim of this study was to identify novel immunoregulatory receptors specifically expressed on TAM. Expression of Slamf9, a member of the signaling lymphocytic-activating molecule (Slam) immunoreceptor family, was found to be upregulated in a gene expression analysis of murine bone marrow-derived macrophages (BMDM) stimulated with tumor-conditioned medium of B16F1 melanoma cells...
September 19, 2018: Cell Death & Disease
Bruno Gomes, Gregory Driessens, Derek Bartlett, Danying Cai, Sandra Cauwenberghs, Stefano Crosignani, Deepak Dalvie, Sofie Denies, Christopher P Dillon, Valeria R Fantin, Jie Guo, Marie-Claire Letellier, Wenlin Li, Karen A Maegley, Reece Marillier, Nichol Miller, Romain Pirson, Virginie Rabolli, Chad Ray, Nicole Streiner, Vince R Torti, Konstantinos Tsaparikos, Benoit J Van den Eynde, Martin Wythes, Li-Chin Yao, Xianxian Zheng, Joseph Tumang, Manfred Kraus
Tumors use Indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites including kynurenine in the tumor microenvironment. This leads to effector T-cell anergy and enhanced Treg function through upregulation of FoxP3...
September 19, 2018: Molecular Cancer Therapeutics
Ravindran Kanesvaran, Raul Cordoba, Ronald Maggiore
Immunotherapy has expanded the therapeutic landscape for advanced cancers, including solid tumors and lymphomas. For many patients with cancer, these agents have been shown to have substantial efficacy and favorable toxicity compared with cytotoxic agents, particularly in the second-line setting. With the advent of anti-PD-1 and anti-PD-L1 checkpoint inhibitors, combination immunotherapy- and chemoimmunotherapy-based strategies have emerged as promising novel regimens to improve cancer-related outcomes. Older adults age 65 or older represent the growing majority of patients diagnosed with cancer...
May 23, 2018: American Society of Clinical Oncology Educational Book
Denis L Jardim, Débora de Melo Gagliato, Razelle Kurzrock
Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program...
September 19, 2018: Integrative Cancer Therapies
Haritha G Reddy, Bryan J Schneider, Andrew W Tai
Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand PD-L1. ICPIs are now approved for the treatment of a wide array of malignancies, with rates of durable responses in the metastatic setting far exceeding what would be expected from conventional chemotherapy. ICPIs have also been associated with rare but serious immune-related adverse events due to over-activation of the immune system that can affect any organ, including the gastrointestinal tract and liver...
September 19, 2018: Clinical and Translational Gastroenterology
Jason M Redman, Seth M Steinberg, James L Gulley
Advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have transformed the treatment landscapes of several malignancies in recent years. Oncologists are now tasked with extending these benefits to a greater number of patients and tumor types. Metastatic castration-resistant prostate cancer (mCRPC) infrequently responds to ICIs, while the cellular vaccine approved for mCRPC, sipuleucel-T, provides a 4-month survival benefit but does not produce clinical responses as monotherapy. However, many novel and generally well-tolerated immune oncology agents with potential for immune synergy and/or additive effects are undergoing clinical development...
September 18, 2018: Journal for Immunotherapy of Cancer
Luke R G Pike, Andrew Bang, Brandon A Mahal, Allison Taylor, Monica Krishnan, Alexander Spektor, Daniel N Cagney, Ayal A Aizer, Brian M Alexander, Osama Rahma, Tracy Balboni, Patrick A Ott, F Stephen Hodi, Jonathan D Schoenfeld
PURPOSE: Therapeutic radiation has conflicting immune effects: radiation (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICI) and whether this impacts outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-lymphocyte-ratio (NTL) in patients being treated with PD-1 directed ICI and associations with survival...
September 15, 2018: International Journal of Radiation Oncology, Biology, Physics
Theresa Westphal, Simon Peter Gampenrieder, Gabriel Rinnerthaler, Richard Greil
Oligometastatic disease characterizes a distinct subgroup of metastatic breast cancer patients that might benefit from different treatment strategies to achieve long-lasting remission and potentially cure. Those long-lasting remissions are reported after locoregional treatment of the primary tumor and all metastatic sites in several case series; however, unlike other tumor entities, prospective data are lacking. Furthermore, tumor eradication by excellent systemic anticancer therapy with novel chemotherapies and targeted agents can lead to long-term survival...
2018: Memo
Jeffrey Yang, Longqin Hu
Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity...
September 14, 2018: Medicinal Research Reviews
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