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Melanoma pd-1

Randi Woodbeck, Andrei I Metelitsa, Karen A Naert
Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced melanoma, with these agents significantly improving survival for patients with metastatic disease. With the increasing use of these agents, the number of adverse reactions secondary to their use has also increased. Sarcoidosis and sarcoid-like reactions are one such immune checkpoint inhibitor-related adverse event. We report a case of sarcoid-like granulomatous tumoral melanosis in a patient on the programmed cell death-1 (PD-1) receptor inhibitor pembrolizumab for metastatic melanoma...
July 2018: American Journal of Dermatopathology
Susanne Horn, Sonia Leonardelli, Antje Sucker, Dirk Schadendorf, Klaus G Griewank, Annette Paschen
Poor clinical responses to checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies in melanoma have recently been associated with acquired IFNγ resistance that protects tumor cells from the antiproliferative and pro-apoptotic cytokine activity. IFNγ-resistant melanoma cells very often lack functional expression of the IFNγ signaling pathway gene JAK2 due to gene deletions or inactivating gene mutations. Analyzing melanoma cell lines (n = 46, applying next-generation targeted sequencing and single nucleotide polymorphism arrays) as well as available genomic data sets from The Cancer Genome Atlas (TCGA) tumor tissue samples (cutaneous melanoma n = 367, lung squamous cell carcinoma n = 501, bladder urothelial carcinoma n = 408, breast invasive carcinoma n = 768, colorectal adenocarcinoma n = 257), we demonstrate that the frequent chromosomal losses of the tumor suppressor CDKN2A in melanoma and other tumor entities enhance the susceptibility to IFNγ resistance by concomitant deletion of the JAK2 gene (odds ratio = 223...
June 1, 2018: Journal of the National Cancer Institute
Tyler P Robin, Robert E Breeze, Derek E Smith, Chad G Rusthoven, Karl D Lewis, Rene Gonzalez, Amanda Brill, Robin Saiki, Kelly Stuhr, Laurie E Gaspar, Sana D Karam, David Raben, Brian D Kavanagh, Sameer K Nath, Arthur K Liu
INTRODUCTION: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery...
June 16, 2018: Journal of Neuro-oncology
Graham Pawelec
Immunosenescence might be expected to reduce the efficacy of checkpoint blockade, which depends on a functionally intact immune system. However, it seems that older melanoma patients may respond better to anti-PD1 treatment than younger patients, possibly due to their having fewer regulatory T-cells relative to CD8+ T-cells within tumour deposits.
June 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Heidi Harjunpää, Stephen J Blake, Elizabeth Ahern, Stacey Allen, Jing Liu, Juming Yan, Viviana Lutzky, Kazuyoshi Takeda, Amy Roman Aguilera, Camille Guillerey, Deepak Mittal, Xian Yang Li, William C Dougall, Mark J Smyth, Michele W L Teng
Multiple non-redundant immunosuppressive pathways co-exist in the tumor microenvironment and their co-targeting can increase clinical responses. Indeed, concurrent blockade of CTLA-4 and PD-1 in patients with advanced melanoma increased clinical responses over monotherapy alone although the frequency and severity of immune related adverse events (irAEs) also increased. Nevertheless, a substantial number of patients still display an innate resistance phenotype and are unresponsive to current approved immunotherapies even when utilized in combination...
2018: Oncoimmunology
Mareike Grees, Adi Sharbi-Yunger, Christos Evangelou, Daniel Baumann, Gal Cafri, Esther Tzehoval, Stefan B Eichmüller, Rienk Offringa, Jochen Utikal, Lea Eisenbach, Viktor Umansky
Despite melanoma immunogenicity and remarkable therapeutic effects of negative immune checkpoint inhibitors, a significant fraction of patients does not respond to current treatments. This could be due to limitations in tumor immunogenicity and profound immunosuppression in the melanoma microenvironment. Moreover, insufficient tumor antigen processing and presentation by dendritic cells (DC) may hamper the development of tumor-specific T cells. Using two genetically engineered mouse melanoma models ( RET and BRAFV600E transgenic mice), in which checkpoint inhibitor therapy alone is not efficacious, we performed proof-of-concept studies with an improved, multivalent DC vaccination strategy based on our recently developed genetic mRNA cancer vaccines...
2018: Oncoimmunology
Xinqi Wu, Anita Giobbie-Hurder, Erin M Connolly, Jingjing Li, Xiaoyun Liao, Mariano Severgnini, Jun Zhou, Scott Rodig, F Stephen Hodi
The combination of CTLA-4 blockade ipilimumab (Ipi) with VEGF-A blocking antibody bevacizumab (Bev) has demonstrated favorable clinical outcomes in patients with advanced melanoma. Galectin-3 (Gal-3) plays a prominent role in tumor growth, metastasis, angiogenesis, and immune evasion. Here we report that Ipi plus Bev (Ipi-Bev) therapy increased Gal-3 antibody titers by 50% or more in approximately one third of treated patients. Antibody responses to Gal-3 were associated with higher complete and partial responses and better overall survival...
2018: Oncoimmunology
Curtis H Kugel, Stephen M Douglass, Marie R Webster, Amanpreet Kaur, Qin Liu, Xiangfan Yin, Sarah A Weiss, Farbod Darvishian, Rami N Al-Rohil, Abibatou Ndoye, Reeti Behera, Gretchen M Alicea, Brett L Ecker, Mitchell Fane, Michael J Allegrezza, Nikolaos Svoronos, Vinit Kumar, Daniel Y Wang, Rajasekharan Somasundaram, Siwen Hu-Lieskovan, Alpaslan Ozgun, Meenhard Herlyn, Jose R Conejo-Garcia, Dmitry Gabrilovich, Erica L Stone, Theodore S Nowicki, Jeffrey Sosman, Rajat Rai, Matteo S Carlino, Georgina V Long, Richard Marais, Antoni Ribas, Zeynep Eroglu, Michael A Davies, Bastian Schilling, Dirk Schadendorf, Wei Xu, Ravi K Amaravadi, Alexander M Menzies, Jennifer L McQuade, Douglas B Johnson, Iman Osman, Ashani T Weeraratna
Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1. Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies. Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy...
June 13, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Lei Wang, Sara J Felts, Virginia P Van Keulen, Adam D Scheid, Matthew S Block, Svetomir N Markovic, Larry R Pease, Yuji Zhang
Genome-wide identification and characterization of long non-coding RNAs (lncRNAs) in individual immune cell lineages helps us better understand the driving mechanisms behind melanoma and advance personalized patient treatment. To elucidate the transcriptional landscape in diverse immune cell types of peripheral blood cells (PBC) in stage IV melanoma, we used whole transcriptome RNA sequencing to profile lncRNAs in CD4+, CD8+, and CD14+ PBC from 132 patient samples. Our integrative computational approach identified 27,625 expressed lncRNAs, 2,744 of which were novel...
June 12, 2018: Cancer Research
Mei-Zhen Zou, Wen-Long Liu, Chu-Xin Li, Di-Wei Zheng, Jin-Yue Zeng, Fan Gao, Jing-Jie Ye, Xian-Zheng Zhang
Hypoxia is reported to participate in tumor progression, promote drug resistance, and immune escape within tumor microenvironment, and thus impair therapeutic effects including the chemotherapy and advanced immunotherapy. Here, a multifunctional biomimetic core-shell nanoplatform is reported for improving synergetic chemotherapy and immunotherapy. Based on the properties including good biodegradability and functionalities, the pH-sensitive zeolitic imidazolate framework 8 embedded with catalase and doxorubicin constructs the core and serves as an oxygen generator and drug reservoir...
June 7, 2018: Small
Na Luo, Luigi Formisano, Paula I Gonzalez-Ericsson, Violeta Sanchez, Phillip T Dean, Susan R Opalenik, Melinda E Sanders, Rebecca S Cook, Carlos L Arteaga, Douglas B Johnson, Justin M Balko
Immunotherapies targeting programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1), dramatically improve the survival of melanoma patients. However, only ∼40% of treated patients demonstrate a clinical response to single-agent anti-PD-1 therapy. An intact tumor response to type-II interferon (i.e. IFN-γ) correlates with response to anti-PD-1, and patients with de novo or acquired resistance may harbor loss-of-function alterations in the JAK/STAT pathway, which lies downstream of the interferon gamma receptor (IFNGR1/2)...
2018: Oncoimmunology
Masood Sadaat, Sekwon Jang
BACKGROUND: Hemophagocytic Lymphohistiocytosis (HLH), a rare but potentially fatal syndrome of immune hyperactivation, may be an under-recognized immune-related adverse event (irAE). Unlike other irAEs, HLH triggered by immune checkpoint blockade is not well described; no particular diagnostic guidelines and treatment regimens exist. The HLH-2004 criteria remain as the common diagnostic guide. For the treatment of HLH, various combinations of chemotherapeutic, immunosuppressive and glucocorticoid agents are used...
June 5, 2018: Journal for Immunotherapy of Cancer
João P Aguiar, Fábio Cardoso Borges, Rodrigo Murteira, Catarina Ramos, Emanuel Gouveia, Maria José Passos, Ana Miranda, Filipa Alves da Costa
Background Toxicity of oncology treatments in real-life patients is frequently disregarded and hence underreported. Objective To characterize adverse events (AEs) of immunotherapy and targeted therapy reported in patients with locally advanced or metastatic melanoma. Setting District Hospital for Cancer treatment (Instituto Português de Oncologia de Lisboa Francisco Gentil). Method A retrospective cohort of melanoma patients was established, comprising adult patients diagnosed with malignant melanoma treated with immunotherapy or targeted therapy...
June 2, 2018: International Journal of Clinical Pharmacy
Yue Lang, Fengna Chu, Donghui Shen, Weiguanliu Zhang, Chao Zheng, Jie Zhu, Li Cui
Inflammasomes are multiprotein complexes that can sense pathogen-associated molecular patterns and damage-associated molecular signals. They are involved in the initiation and development of inflammation via activation of IL-1 β and IL-18. Many recent studies suggest a strong correlation between inflammasomes and neurological diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), and Parkinson's disease (PD). Several components of inflammasomes, such as nucleotide-binding oligomerization domain- (NOD-) like receptor, absent in melanoma 2- (AIM2-) like receptors (ALRs), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1, as well as the upstream factors and downstream effectors, are associated with the initiation and development of MS and its animal model, experimental autoimmune encephalomyelitis...
2018: Mediators of Inflammation
Panagiotis Mastorakos, Zhiyuan Xu, James Yu, Judith Hess, Jack Qian, Ajay Chatrath, Davis G Taylor, Douglas Kondziolka, Ronald Warnick, Veronica Chiang, Jason Sheehan
BACKGROUND: The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM). OBJECTIVE: To further investigate the effectiveness of this combined treatment regimen. METHODS: In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified...
May 29, 2018: Neurosurgery
Li-Li Guo, Gang-Cheng Wang, Peng-Jie Li, Cui-Mei Wang, Lin-Bo Liu
Viral vectors represent a potential strategy for the treatment of human malignant tumors. Currently, recombinant adenovirus vectors are commonly used as gene therapy vehicles, as it possesses a proven safety profile in normal human cells. The recombinant adenovirus system has an ability to highly express exogenous genes and increase the stability of the carrier, which is only transiently expressed in the host cell genome, without integrating. Malignant melanoma cells are produced by the skin, and melanocyte tumors that exhibit higher malignant degrees lead to earlier transfer and higher mortality...
June 2018: Experimental and Therapeutic Medicine
Winson S Ho, Herui Wang, Dominic Maggio, John S Kovach, Qi Zhang, Qi Song, Francesco M Marincola, John D Heiss, Mark R Gilbert, Rongze Lu, Zhengping Zhuang
Mounting evidence suggests that inhibition of protein phosphatase-2A (PP2A), a serine/threonine phosphatase, could enhance anticancer immunity. However, drugs targeting PP2A are not currently available. Here, we report that a PP2A inhibitor, LB-100, when combined with anti-PD-1 (aPD-1) blockade can synergistically elicit a durable immune-mediated antitumor response in a murine CT26 colon cancer model. This effect is T-cell dependent, leading to regression of a significant proportion of tumors. Analysis of tumor lymphocytes demonstrates enhanced effector T-cell and reduced suppressive regulatory T-cell infiltration...
May 29, 2018: Nature Communications
Feng Xu, Tianqiang Jin, Yuwen Zhu, Chaoliu Dai
Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan...
May 29, 2018: Journal of Experimental & Clinical Cancer Research: CR
Michael Constantin Kirchberger, Selma Ugurel, Johanna Mangana, Markus Valentin Heppt, Thomas Kurt Eigentler, Carola Berking, Dirk Schadendorf, Gerold Schuler, Reinhard Dummer, Lucie Heinzerling
BACKGROUND: Melanoma harbours genetic alterations in genes such as BRAF, NRAS and KIT. Activating NRAS mutations are present in about 20% of melanomas. Even though BRAF mutations can be effectively targeted with specific inhibitors, this approach has proven more challenging in cases of NRAS mutations. Previous reports suggested that immunotherapy might be more successful in NRAS-mutated compared to BRAF-mutated or BRAF/NRAS wildtype melanoma. PATIENTS AND METHODS: In this study, overall survival and response to anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilimumab) therapy of 364 patients with metastatic melanoma were assessed comparing 236 NRAS-mutated patients with 128 NRAS wildtype patients...
May 26, 2018: European Journal of Cancer
Marie-Léa Gauci, Philippe Boudou, Barouyr Baroudjian, Tiphaine Vidal-Trecan, Laetitia Da Meda, Isabelle Madelaine-Chambrin, Nicole Basset-Seguin, Martine Bagot, Cécile Pages, Samia Mourah, Matthieu Resche-Rigon, Sylvine Pinel, Marion Sassier, Franck Rouby, Pirayeh Eftekhari, Céleste Lebbé, Jean-François Gautier
Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital...
May 28, 2018: Cancer Immunology, Immunotherapy: CII
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