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Journal for Immunotherapy of Cancer

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https://www.readbyqxmd.com/read/29925431/inhibition-of-wee1-kinase-and-cell-cycle-checkpoint-activation-sensitizes-head-and-neck-cancers-to-natural-killer-cell-therapies
#1
Jay Friedman, Megan Morisada, Lillian Sun, Ellen C Moore, Michelle Padget, James W Hodge, Jeffrey Schlom, Sofia R Gameiro, Clint T Allen
BACKGROUND: Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined. METHODS: Tumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis...
June 21, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29921320/phase-ia-study-of-the-indoleamine-2-3-dioxygenase-1-ido1-inhibitor-navoximod-gdc-0919-in-patients-with-recurrent-advanced-solid-tumors
#2
Asha Nayak-Kapoor, Zhonglin Hao, Ramses Sadek, Robin Dobbins, Lisa Marshall, Nicholas N Vahanian, W Jay Ramsey, Eugene Kennedy, Mario R Mautino, Charles J Link, Ray S Lin, Stephanie Royer-Joo, Xiaorong Liang, Laurent Salphati, Kari M Morrissey, Sami Mahrus, Bruce McCall, Andrea Pirzkall, David H Munn, John E Janik, Samir N Khleif
BACKGROUND: Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. METHODS: This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule...
June 20, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29921314/oxidized-lipids-keep-heat-shock-chaperones-busy-new-insights-on-the-deficiencies-of-tumour-associated-dendritic-cells
#3
EDITORIAL
Paula Nunes-Hasler
In a recent publication in Nature Communications the group of Dr. Dmitry Gabrilovich takes us one step closer to understanding why lipid accumulation impairs the function of tumour-associated dendritic cells (DCs). In this study, the authors present two surprising and significant findings. First, they show that in mouse DCs oxidized lipids function as a sink that traps the heat shock chaperone HSP70, a molecular target of emerging anti-cancer strategies. Secondly, they find that HSP70 in turn regulates the trafficking of peptide-loaded major histocompatibility complex class I (pMHC-I) molecules, a complex that triggers the proliferation of cancer-killing T cells...
June 20, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29921327/enhanced-susceptibility-of-cancer-cells-to-oncolytic-rhabdo-virotherapy-by-expression-of-nodamura-virus-protein-b2-as-a-suppressor-of-rna-interference
#4
Donald Bastin, Amelia S Aitken, Adrian Pelin, Larissa A Pikor, Mathieu J F Crupi, Michael S Huh, Marie-Claude Bourgeois-Daigneault, John C Bell, Carolina S Ilkow
Antiviral responses are barriers that must be overcome for efficacy of oncolytic virotherapy. In mammalian cells, antiviral responses involve the interferon pathway, a protein-signaling cascade that alerts the immune system and limits virus propagation. Tumour-specific defects in interferon signaling enhance viral infection and responses to oncolytic virotherapy, but many human cancers are still refractory to oncolytic viruses. Given that invertebrates, fungi and plants rely on RNA interference pathways for antiviral protection, we investigated the potential involvement of this alternative antiviral mechanism in cancer cells...
June 19, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29914578/near-complete-response-to-pembrolizumab-in-microsatellite-stable-metastatic-sebaceous-carcinoma
#5
Evidio Domingo-Musibay, Paari Murugan, Alessio Giubellino, Sandeep Sharma, Daniel Steinberger, Jianling Yuan, Matthew A Hunt, Emil Lou, Jeffrey S Miller
BACKGROUND: Sebaceous carcinoma is an aggressive adnexal skin tumor with a predilection for the eyelids and sebaceous glands of the head and neck. CASE PRESENTATION: A 73 year-old man presented with confusion and was found to have widely disseminated sebaceous carcinoma with metastases to brain, lungs, liver, bowel, lymph nodes, and bone. Following initial treatment of the brain metastases with surgery he received post-operative radiosurgery. He then began systemic immunotherapy with pembrolizumab...
June 19, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29914571/targeting-adenosine-for-cancer-immunotherapy
#6
Robert D Leone, Leisha A Emens
Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment...
June 18, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29907163/cytokine-release-syndrome
#7
REVIEW
Alexander Shimabukuro-Vornhagen, Philipp Gödel, Marion Subklewe, Hans Joachim Stemmler, Hans Anton Schlößer, Max Schlaak, Matthias Kochanek, Boris Böll, Michael S von Bergwelt-Baildon
During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS)...
June 15, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29898788/immunomodulatory-activities-of-pixatimod-emerging-nonclinical-and-clinical-data-and-its-potential-utility-in-combination-with-pd-1-inhibitors
#8
Edward Hammond, Nicole M Haynes, Carleen Cullinane, Todd V Brennan, Darryn Bampton, Paul Handley, Tomislav Karoli, Fleur Lanksheer, Liwen Lin, Yiping Yang, Keith Dredge
BACKGROUND: Pixatimod (PG545) is a novel clinical-stage immunomodulatory agent capable of inhibiting the infiltration of tumor-associated macrophages (TAMs) yet also stimulate dendritic cells (DCs), leading to activation of natural killer (NK) cells. Preclinically, pixatimod inhibits heparanase (HPSE) which may be associated with its inhibitory effect on TAMs whereas its immunostimulatory activity on DCs is through the MyD88-dependent TLR9 pathway. Pixatimod recently completed a Phase Ia monotherapy trial in advanced cancer patients...
June 14, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29898784/rhabdomyolysis-during-high-dose-interleukin-2-treatment-of-metastatic-melanoma-after-sequential-immunotherapies-a-case-report
#9
Joseph I Clark, Shams Bufalino, Shruti Singh, Ewa Borys
BACKGROUND: The treatment options for metastatic malignant melanoma have drastically changed recently,including the increased use of immunotherapeutic agents that offer significant responses. Accordingly, it hasbecome common for sequential administration of such agents. Despite this, no guidelines exist on propersequencing or potential unique toxicities associated with such sequencing. CASE PRESENTATION: We describe here the first incidence, to our knowledge, of clinically significant rhabdomyolysis associated with high-dose interleukin-2 after prior treatment with ipilimumab, genetically engineered T-cell therapy and subsequent single agent pembrolizumab in a patient with BRAF wild type metastatic malignant melanoma...
June 14, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29898782/expression-of-human-cd46-and-trans-complementation-by-murine-adenovirus-1-fails-to-allow-productive-infection-by-a-group-b-oncolytic-adenovirus-in-murine-cancer-cells
#10
Janet Lei, Egon J Jacobus, William K Taverner, Kerry D Fisher, Silvio Hemmi, Katy West, Lorna Slater, Fred Lilley, Alice Brown, Brian Champion, Margaret R Duffy, Len W Seymour
BACKGROUND: Oncolytic viruses are currently experiencing accelerated development in several laboratories worldwide, with some forty-seven clinical trials currently recruiting. Many oncolytic viruses combine targeted cytotoxicity to cancer cells with a proinflammatory cell lysis. Due to their additional potential to express immunomodulatory transgenes, they are also often known as oncolytic viral vaccines. However, several types of oncolytic viruses are human-specific and the lack of suitable immune-competent animal models complicates biologically relevant evaluation of their vaccine potential...
June 13, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29898781/thoracic-and-cutaneous-sarcoid-like-reaction-associated-with-anti-pd-1-therapy-longitudinal-monitoring-of-pd-1-and-pd-l1-expression-after-stopping-treatment
#11
Léa Paolini, Caroline Poli, Simon Blanchard, Thierry Urban, Anne Croué, Marie-Christine Rousselet, Sarah Le Roux, Nathalie Labarrière, Pascale Jeannin, José Hureaux
BACKGROUND: Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis. CASE PRESENTATION: We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb...
June 13, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29891009/dexamethasone-induced-immunosuppression-mechanisms-and-implications-for-immunotherapy
#12
Amber J Giles, Marsha-Kay N D Hutchinson, Heather M Sonnemann, Jinkyu Jung, Peter E Fecci, Nivedita M Ratnam, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Caitlin M Reid, Deric M Park, Mark R Gilbert
BACKGROUND: Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment...
June 11, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29871672/effect-of-neoadjuvant-chemotherapy-on-the-immune-microenvironment-in-non-small-cell-lung-carcinomas-as-determined-by-multiplex-immunofluorescence-and-image-analysis-approaches
#13
Edwin R Parra, Pamela Villalobos, Carmen Behrens, Mei Jiang, Apar Pataer, Stephen G Swisher, William N William, Jiexin Zhang, Jack Lee, Tina Cascone, John V Heymach, Marie-Andrée Forget, Cara Haymaker, Chantale Bernatchez, Neda Kalhor, Annikka Weissferdt, Cesar Moran, Jianjun Zhang, Ara Vaporciyan, Don L Gibbons, Boris Sepesi, Ignacio I Wistuba
BACKGROUND: The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT)...
June 6, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29871698/hemophagocytic-lymphohistiocytosis-with-immunotherapy-brief-review-and-case-report
#14
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
https://www.readbyqxmd.com/read/29871670/immune-oncology-immune-responsiveness-and-the-theory-of-everything
#15
Tolga Turan, Deepti Kannan, Maulik Patel, J Matthew Barnes, Sonia G Tanlimco, Rongze Lu, Kyle Halliwill, Sarah Kongpachith, Douglas E Kline, Wouter Hendrickx, Alessandra Cesano, Lisa H Butterfield, Howard L Kaufman, Thomas J Hudson, Davide Bedognetti, Francesco Marincola, Josue Samayoa
Anti-cancer immunotherapy is encountering its own checkpoint. Responses are dramatic and long lasting but occur in a subset of tumors and are largely dependent upon the pre-existing immune contexture of individual cancers. Available data suggest that three landscapes best define the cancer microenvironment: immune-active, immune-deserted and immune-excluded. This trichotomy is observable across most solid tumors (although the frequency of each landscape varies depending on tumor tissue of origin) and is associated with cancer prognosis and response to checkpoint inhibitor therapy (CIT)...
June 5, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29866197/radiation-therapy-and-pd-1-pd-l1-blockade-the-clinical-development-of-an-evolving-anticancer-combination
#16
REVIEW
Jun Gong, Thang Q Le, Erminia Massarelli, Andrew E Hendifar, Richard Tuli
Several inhibitors of programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved as a form of immunotherapy for multiple cancers. Ionizing radiation therapy (RT) has been shown to enhance the priming and effector phases of the antitumor T-cell response rendering it an attractive therapy to combine with PD-1/PD-L1 inhibitors. Preclinical data support the rational combination of the 2 modalities and has paved way for the clinical development of the combination across a spectrum of cancers...
June 4, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29866166/correction-to-discovery-and-preclinical-characterization-of-the-antagonist-anti-pd-l1-monoclonal-antibody-ly3300054
#17
Yiwen Li, Carmine Carpenito, George Wang, David Surguladze, Amelie Forest, Maria Malabunga, Mary Murphy, Yiwei Zhang, Andreas Sonyi, Darin Chin, Douglas Burtrum, Ivan Inigo, Anthony Pennello, Leyi Shen, Laurent Malherbe, Xinlei Chen, Gerald Hall, Jaafar N Haidar, Dale L Ludwig, Ruslan D Novosiadly, Michael Kalos
Unfortunately, after publication of this article [1], it was noticed that corrections to the legends of Figs. 1 and 2 were not correctly incorporated. The correct legends can be seen below.
June 4, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29866156/targeting-the-tgf%C3%AE-pathway-with-galunisertib-a-tgf%C3%AE-ri-small-molecule-inhibitor-promotes-anti-tumor-immunity-leading-to-durable-complete-responses-as-monotherapy-and-in-combination-with-checkpoint-blockade
#18
Rikke B Holmgaard, David A Schaer, Yanxia Li, Stephen P Castaneda, Mary Y Murphy, Xiaohong Xu, Ivan Inigo, Julie Dobkin, Jason R Manro, Philip W Iversen, David Surguladze, Gerald E Hall, Ruslan D Novosiadly, Karim A Benhadji, Gregory D Plowman, Michael Kalos, Kyla E Driscoll
BACKGROUND: TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ's immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS: In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation...
June 4, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29848375/an-update-on-the-society-for-immunotherapy-of-cancer-consensus-statement-on-tumor-immunotherapy-for-the-treatment-of-cutaneous-melanoma-version-2-0
#19
Ryan J Sullivan, Michael B Atkins, John M Kirkwood, Sanjiv S Agarwala, Joseph I Clark, Marc S Ernstoff, Leslie Fecher, Thomas F Gajewski, Brian Gastman, David H Lawson, Jose Lutzky, David F McDermott, Kim A Margolin, Janice M Mehnert, Anna C Pavlick, Jon M Richards, Krista M Rubin, William Sharfman, Steven Silverstein, Craig L Slingluff, Vernon K Sondak, Ahmad A Tarhini, John A Thompson, Walter J Urba, Richard L White, Eric D Whitman, F Stephen Hodi, Howard L Kaufman
BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available...
May 30, 2018: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/29848371/in-field-and-abscopal-response-after-short-course-radiation-therapy-in-patients-with-metastatic-merkel-cell-carcinoma-progressing-on-pd-1-checkpoint-blockade-a-case-series
#20
Melody J Xu, Susan Wu, Adil I Daud, Siegrid S Yu, Sue S Yom
BACKGROUND: Patients with metastatic Merkel cell carcinoma (mMCC) who experience disease progression on immunotherapy have limited additional standard options. Given evidence of synergism between radiation therapy (RT) and immunotherapy, two patients progressing on PD-1 inhibition were referred for short-course RT. CASE PRESENTATION: Two patients were found to have progressive mMCC on PD-1 inhibitor therapy and were treated with single-fraction palliative RT. Both patients were observed to have local control at irradiated regions, as well as durable abscopal response at unirradiated, out-of-field, sites of metastatic disease...
May 30, 2018: Journal for Immunotherapy of Cancer
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