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Immune checkpoint therapy

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https://www.readbyqxmd.com/read/28921644/clinical-pharmacology-considerations-for-the-development-of-immune-checkpoint-inhibitors
#1
Jennifer Sheng, Shivani Srivastava, Kinjal Sanghavi, Zheng Lu, Brian J Schmidt, Akintunde Bello, Manish Gupta
Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28919987/programmed-death-ligand-1-pd-l1-expression-influences-the-immune-tolerogenic-microenvironment-in-antiretroviral-therapy-refractory-kaposi-s-sarcoma-a-pilot-study
#2
Salvinia Mletzko, David J Pinato, Rebecca C Robey, Alessia Dalla Pria, Peter Benson, Nesrina Imami, Mark Bower
Upregulation of programmed death ligand 1 (PD-L1) is a mechanism of immune escape utilized by a variety of tumors. PD-L1 expression in tumor cells or in the surrounding infiltrate correlates with clinical responsiveness to novel therapies targeting the PD-1/PD-L1 immune checkpoint. In the context of HIV-1 infection, Kaposi's sarcoma (KS) is largely responsive to restoration of immunity following combination antiretroviral therapy (cART), but there is a subset that is not. We hypothesized that this subset of cART-refractory KS may utilize the PD-L1 pathway of immune escape...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919986/immune-biomarkers-for-prognosis-and-prediction-of-responses-to-immune-checkpoint-blockade-in-cutaneous-melanoma
#3
REVIEW
Nicolas Jacquelot, Jonathan M Pitt, David P Enot, Maria Paula Roberti, Connie P M Duong, Sylvie Rusakiewicz, Alexander M Eggermont, Laurence Zitvogel
Existing clinical, anatomopathological and molecular biomarkers fail to reliably predict the prognosis of cutaneous melanoma. Biomarkers for determining which patients receive adjuvant therapies are needed. The emergence of new technologies and the discovery of new immune populations with different prognostic values allow the immune network in the tumor to be better understood. Importantly, new molecules identified and expressed by immune cells have been shown to reduce the antitumor immune efficacy of therapies, prompting researchers to develop antibodies targeting these so-called "immune checkpoints", which have now entered the oncotherapeutic armamentarium...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919706/profile-of-pembrolizumab-in-the-treatment-of-head-and-neck-squamous-cell-carcinoma-design-development-and-place-in-therapy
#4
REVIEW
Sulsal Haque, Mahender Yellu, Jaskirat Randhawa, Nooshin Hashemi-Sadraei
Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy worldwide, and despite advances in cytotoxic, surgical and radiation techniques, outcomes are still poor in those with both locally advanced and metastatic diseases. The need for development of better therapeutics along with a greater understanding of the relationship between the immune system and malignancies has led to a new therapeutic modality, immune modulators, particularly checkpoint inhibitors in HNSCC. It is now well recognized that HNSCC circumvents crucial pathways utilized by the immune system to escape surveillance...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28918995/cutaneous-adverse-events-of-targeted-therapies-for-hematolymphoid-malignancies
#5
REVIEW
Julia D Ransohoff, Bernice Y Kwong
The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies...
July 14, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28917596/response-rate-to-chemotherapy-after-immune-checkpoint-inhibition-in-metastatic-urothelial-cancer
#6
Bernadett Szabados, Nick van Dijk, Yen Zhi Tang, Michiel van der Heijden, Akhila Wimalasingham, Alfonso Gomez de Liano, Simon Chowdhury, Simon Hughes, Sarah Rudman, Mark Linch, Thomas Powles
Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described (n=28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1...
September 13, 2017: European Urology
https://www.readbyqxmd.com/read/28917578/emerging-biomarkers-for-cancer-immunotherapy-in-melanoma
#7
REVIEW
Margaret L Axelrod, Douglas B Johnson, Justin M Balko
The treatment and prognosis of metastatic melanoma has changed substantially since the advent of novel immune checkpoint inhibitors (ICI), agents that enhance the anti-tumor immune response. Despite the success of these agents, clinically actionable biomarkers to aid patient and regimen selection are lacking. Herein, we summarize and review the evidence for candidate biomarkers of response to ICIs in melanoma. Many of these candidates can be examined as parts of a known molecular pathway of immune response, while others are clinical in nature...
September 13, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28917247/the-optimism-surrounding-stereotactic-body-radiation-therapy-and-immunomodulation
#8
Hannah Tharmalingam, Peter J Hoskin
In recent years, rapidly evolving radiation techniques have enabled the precise delivery of very high doses of radiation to local targets with stereotactic ablative body radiotherapy (SABR). In addition to its direct cytotoxicity, radiation and in particular SABR has powerful immunomodulatory effects resulting in immunogenic cell death and potentiation of the anti-tumour immune response. However, due to the immunosuppressive nature of non-irradiated sites of metastases, radiotherapy alone is seldom sufficient to induce the systemic response required for distant tumour rejection...
September 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28916903/merkel-cell-carcinoma-epidemiology-pathogenesis-diagnosis-and-therapy
#9
REVIEW
Teresa Amaral, Ulrike Leiter, Claus Garbe
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer with a neuroendocrine phenotype. Incidence varies according to the geographic regions but is overall increasing. Different risk factors have been identified namely advanced age, immunosuppression, and ultraviolet light exposure. An association between MCC and polyomavirus infection is known. However, the exact mechanism that leads to carcinogenesis is yet to be fully understood. Surgery when feasible is the recommended treatment for localized disease, followed by adjuvant radiation or chemoradiation...
September 16, 2017: Reviews in Endocrine & Metabolic Disorders
https://www.readbyqxmd.com/read/28916749/checkpoint-blockade-immunotherapy-reshapes-the-high-dimensional-phenotypic-heterogeneity-of-murine-intratumoural-neoantigen-specific-cd8-t-cells
#10
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/28916658/t-cells-deficient-in-diacylglycerol-kinase-%C3%AE-are-resistant-to-pd-1-inhibition-and-help-create-persistent-host-immunity-to-leukemia
#11
Weiqing Jing, Jill Alane Gershan, Sandra Holzhauer, James Weber, Katie Palen, Laura McOlash, Kirthi Pulakanti, Erin Wesley, Sridhar Rao, Bryon D Johnson, Matthew J Riese
Efforts to improve the efficacy of adoptive T cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the anti-leukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase-zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ-/-) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28916371/ramucirumab-plus-docetaxel-versus-placebo-plus-docetaxel-in-patients-with-locally-advanced-or-metastatic-urothelial-carcinoma-after-platinum-based-therapy-range-a-randomised-double-blind-phase-3-trial
#12
Daniel P Petrylak, Ronald de Wit, Kim N Chi, Alexandra Drakaki, Cora N Sternberg, Hiroyuki Nishiyama, Daniel Castellano, Syed Hussain, Aude Fléchon, Aristotelis Bamias, Evan Y Yu, Michiel S van der Heijden, Nobuaki Matsubara, Boris Alekseev, Andrea Necchi, Lajos Géczi, Yen-Chuan Ou, Hasan Senol Coskun, Wen-Pin Su, Miriam Hegemann, Ivor J Percent, Jae-Lyun Lee, Marcello Tucci, Andrey Semenov, Fredrik Laestadius, Avivit Peer, Giampaolo Tortora, Sufia Safina, Xavier Garcia Del Muro, Alejo Rodriguez-Vida, Irfan Cicin, Hakan Harputluoglu, Ryan C Widau, Astra M Liepa, Richard A Walgren, Oday Hamid, Annamaria H Zimmermann, Katherine M Bell-McGuinn, Thomas Powles
BACKGROUND: Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population. METHODS: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy...
September 12, 2017: Lancet
https://www.readbyqxmd.com/read/28916225/stereotactic-radiosurgery-of-early-melanoma-brain-metastases-after-initiation-of-anti-ctl-4-treatment-is-associated-with-improved-intracranial-control
#13
Yi An, Wen Jiang, Betty Y S Kim, Jack M Qian, Chad Tang, Penny Fang, Jennifer Logan, Neil M D'Souza, Lauren E Haydu, Xin A Wang, Kenneth R Hess, Harriet Kluger, Isabella C Glitza, Anita Mahajan, James W Welsh, Steven H Lin, James B Yu, Michael A Davies, Patrick Hwu, Erik P Sulman, Paul D Brown, Veronica L S Chiang, Jing Li
BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy...
September 12, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28915646/interleukin-15-stimulates-natural-killer-cell-mediated-killing-of-both-human-pancreatic-cancer-and-stellate-cells
#14
Jonas R M Van Audenaerde, Jorrit De Waele, Elly Marcq, Jinthe Van Loenhout, Eva Lion, Johan M J Van den Bergh, Ralf Jesenofsky, Atsushi Masamune, Geert Roeyen, Patrick Pauwels, Filip Lardon, Marc Peeters, Evelien L J Smits
Pancreatic ductal adenocarcinoma (PDAC) is the 4(th) leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC)...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28915590/combination-of-desi2-and-ip10-gene-therapy-significantly-improves-therapeutic-efficacy-against-murine-carcinoma
#15
Chao Lin, HuaYing Yan, Jun Yang, Lei Li, Mei Tang, Xinyu Zhao, Chunlai Nie, Na Luo, Yuquan Wei, Zhu Yuan
DESI2 (also known as PNAS-4) is a novel pro-apoptotic gene activated during the early response to DNA damage. We previously reported that overexpression of DESI2 induces S phase arrest and apoptosis by activating checkpoint kinases. The present study was designed to test whether combination of DESI2 and IP10 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and IP10 was encapsulated with DOTAP/Cholesterol nanoparticle. Immunocompetent mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the complex...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28914644/systemic-therapy-in-advanced-melanoma-integrating-targeted-therapy-and-immunotherapy-into-clinical-practice
#16
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/28913723/therapeutic-implications-of-the-molecular-and-immune-landscape-of-triple-negative-breast-cancer
#17
REVIEW
Ana C Gregório, Manuela Lacerda, Paulo Figueiredo, Sérgio Simões, Sérgio Dias, João Nuno Moreira
Treatment and management of breast cancer imposes a heavy burden on public health care, and incidence rates continue to increase. Breast cancer is the most common female neoplasia and primary cause of death among women worldwide. The recognition of breast cancer as a complex and heterogeneous disease, comprising different molecular entities, was a landmark in our understanding of this malignancy. Valuing the impact of the molecular characteristics on tumor behavior enabled a better assessment of a patient's prognosis and increased the predictive power to therapeutic response and clinical outcome...
September 14, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28913619/bile-duct-obstruction-in-a-patient-treated-with-nivolumab-as-second-line-chemotherapy-for-advanced-non-small-cell-lung-cancer-a-case-report
#18
Jumpei Kashima, Yusuke Okuma, Ryoko Shimizuguchi, Kazuro Chiba
Immune checkpoint inhibitors (ICIs) are becoming a standard therapy for non-small-cell lung cancer in the advanced stage. As these ICIs become widely available in clinical practice, immune-related adverse effects will become more common. Here we report a patient with lung adenocarcinoma who was treated with nivolumab and developed obstruction because of biliary inflammation. A 63-year-old Japanese man having lung adenocarcinoma with pleural dissemination complained of epigastric pain on the fifth cycle of nivolumab...
September 14, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28912399/-adoptive-cell-therapy-with-immune-checkpoint-blockade
#19
Atsushi Aruga
Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene-modified T cells in recent years. The effector cells mostly express PD-1, therefore the cytotoxic reactivity of the effector cells are inhibited by PD-L1...
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28912397/-combination-therapy-of-immune-checkpoint-inhibitors
#20
Shigehisa Kitano
Recently, monotherapies of immune checkpoint inhibitor have been approved for some malignant tumors such as advanced melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin lymphoma, head and neck cancer in Japan. As the next step, to aim improvement of the clinical benefit, development of combination immunotherapies including immune checkpoint inhibitors are ongoing. In this chapter, recent strategies of clinical development of combination immunotherapy are described.
September 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
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