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https://www.readbyqxmd.com/read/28938530/cd3xpdl1-bi-specific-t-cell-engager-bite-simultaneously-activates-t-cells-and-nkt-cells-kills-pdl1-tumor-cells-and-extends-the-survival-of-tumor-bearing-humanized-mice
#1
Lucas A Horn, Nicholas G Ciavattone, Ryan Atkinson, Netsanet Woldergerima, Julia Wolf, Virginia K Clements, Pratima Sinha, Munanchu Poudel, Suzanne Ostrand-Rosenberg
Bi-specific T cell engagers (BiTEs) activate T cells through CD3 and target activated T cells to tumor-expressed antigens. BiTEs have shown therapeutic efficacy in patients with liquid tumors; however, they do not benefit all patients. Anti-tumor immunity is limited by Programmed Death 1 (PD1) pathway-mediated immune suppression, and patients who do not benefit from existing BiTES may be non-responders because their T cells are anergized via the PD1 pathway. We have designed a BiTE that activates and targets both T cells and NKT cells to PDL1(+) cells...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935468/function-and-regulation-of-lag3-on-cd4-cd25-t-cells-in-non-small-cell-lung-cancer
#2
Qin-Yun Ma, Da-Yu Huang, Hui-Jun Zhang, Shaohua Wang, Xiao-Feng Chen
LAG3 is a surface molecule found on a subset of immune cells. The precise function of LAG3 appears to be context-dependent. In this study, we investigated the effect of LAG3 on CD4(+)CD25(-) T cells from non-small cell lung cancer (NSCLC) patients. We found that in the peripheral blood mononuclear cells of NSCLC patients, LAG3 was significantly increased in CD4(+) T cells directly ex vivo and primarily in the CD4(+)CD25(-) fraction, which was regulated by prolonged TCR stimulation and the presence of IL-27...
September 19, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28932645/intratumor-heterogeneity-of-immune-checkpoints-in-primary-renal-cell-cancer-focus-on-hla-g-ilt2-ilt4
#3
Nathalie Rouas-Freiss, Joel LeMaoult, Jérôme Verine, Diana Tronik-Le Roux, Stéphane Culine, Christophe Hennequin, François Desgrandchamps, Edgardo D Carosella
The establishment and maintenance of anti-tumor immune responses are the objectives of cancer immunotherapy. Despite recent promising advances, the effectiveness of these approaches has been limited by the multiple immunosuppressive mechanisms developed by tumors (checkpoint). The aim of the present study was to demonstrate intratumor heterogeneity at the levels of immune escape strategies and tumor-host relationships. We focused on well-known checkpoints such as PD1/PDL1 and on a new checkpoint involving HLA-G and its receptors ILT2/ILT4...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28932636/cd103-tumor-infiltrating-lymphocytes-are-tumor-reactive-intraepithelial-cd8-t-cells-associated-with-prognostic-benefit-and-therapy-response-in-cervical-cancer
#4
Fenne L Komdeur, Thalina M Prins, Stephanie van de Wall, Annechien Plat, G Bea A Wisman, Harry Hollema, Toos Daemen, David N Church, Marco de Bruyn, Hans W Nijman
Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells. To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460)...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28932634/pd1-positive-tumor-infiltrating-lymphocytes-are-associated-with-poor-clinical-outcome-after-pulmonary-metastasectomy-for-colorectal-cancer
#5
Dagmar Kollmann, Thomas Schweiger, Stefan Schwarz, Desislava Ignatova, Yun-Tsan Chang, Gerrit Lewik, Sebastian F Schoppmann, Wolfram Hoetzenecker, Walter Klepetko, Emmanuella Guenova, Konrad Hoetzenecker
Pulmonary metastasectomy (PM) is routinely performed in colorectal cancer (CRC) patients with oligometastatic spreading to the lungs. Patients with an aggressive tumor phenotype should be excluded from PM, since its benefit is outweighed by early tumor recurrence and impaired prognosis. Expression of PD-1 and its ligands are prognostic factors in a variety of primary tumors. However, their impact on patients' outcome in the setting of PM for CRC has not been evaluated before. 53 CRC patients with pulmonary metastases receiving PM with curative intent were included in this study...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28931635/a-computational-multiscale-agent-based-model-for-simulating-spatio-temporal-tumour-immune-response-to-pd1-and-pdl1-inhibition
#6
Chang Gong, Oleg Milberg, Bing Wang, Paolo Vicini, Rajesh Narwal, Lorin Roskos, Aleksander S Popel
When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy...
September 2017: Journal of the Royal Society, Interface
https://www.readbyqxmd.com/read/28925793/sequential-administration-of-mva-based-vaccines-and-pd-1-pd-l1-blocking-antibodies-confers-measurable-benefits-on-tumor-growth-and-survival-preclinical-studies-with-mva-%C3%AE-gal-and-mva-muc1-tg4010-in-a-murine-tumor-model
#7
Christelle Remy-Ziller, Christine Thioudellet, Julie Hortelano, Murielle Gantzer, Virginie Nourtier, Marie-Christine Claudepierre, Benoit Sansas, Xavier Préville, Kaïdre Bendjama, Eric Quemeneur, Karola Rittner
TG4010, a Modified Vaccinia virus Ankara (MVA) expressing human mucin1 (MUC1) has demonstrated clinical benefit for patients suffering from advanced non-small cell lung cancer (NSCLC) in combination with chemotherapy. To support its development, preclinical experiments were performed with either TG4010 or β-galactosidase-encoding MVA vector (MVA-βgal) in mice presenting tumors in the lung. Tumor growth was obtained after intravenous injection of CT26 murine colon cancer cells, engineered to express either MUC1 or βgal...
September 19, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/28892775/challenges-and-perspectives-in-the-immunotherapy-of-hodgkin-lymphoma
#8
REVIEW
Jean-Marie Michot, Julien Lazarovici, David Ghez, Alina Danu, Christophe Fermé, Amélie Bigorgne, Vincent Ribrag, Aurélien Marabelle, Sandrine Aspeslagh
Hodgkin lymphoma (HL) was one of the first few cancers to be cured first with radiotherapy alone and then with a combination of chemotherapy and radiotherapy. Around 80% of the patients with HL will be cured by first-line therapy. However, the ionising radiation not only produces cytotoxicity but also induces alterations in the microenvironment, and patients often struggle with the long-term consequences of these treatments, such as cardiovascular disorders, lung diseases and secondary malignancies. Hence, it is essential to improve treatments while avoiding delayed side-effects...
September 8, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28884747/adverse-prognostic-value-of-pd-l1-expression-in-primary-resected-pulmonary-squamous-cell-carcinomas-and-paired-mediastinal-lymph-node-metastases
#9
Manuel D Keller, Christina Neppl, Yasin Irmak, Sean R Hall, Ralph A Schmid, Rupert Langer, Sabina Berezowska
Immunohistochemical assessment of programmed cell death (PD)-ligand 1 (PD-L1) expression in lung cancer in the context of therapeutically targeting the PD1/PD-L1 axis is still controversially discussed. This includes the comparability of antibody clones, prognostic value, and discrepancies between primary tumors and metastases. We assessed tumoral PD-L1 expression using clones E1L3N and SP142 in 372 primary resected pulmonary squamous cell carcinomas, including 40 paired N2 lymph node metastases, in relation with clinico-pathological parameters...
September 8, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28881701/pd1-signal-transduction-pathways-in-t-cells
#10
REVIEW
Hugo Arasanz, Maria Gato-Cañas, Miren Zuazo, Maria Ibañez-Vea, Karine Breckpot, Grazyna Kochan, David Escors
The use of immune checkpoint inhibitors for the treatment of cancer is revolutionizing oncology. Amongst these therapeutic agents, antibodies that block PD-L1/PD1 interactions between cancer cells and T cells are demonstrating high efficacies and low toxicities. Despite all the recent advances, very little is yet known on the molecular intracellular signaling pathways regulated by either PD-L1 or PD1. Here we review the current knowledge on PD1-dependent intracellular signaling pathways, and the consequences of disrupting PD1 signal transduction...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881692/cabazitaxel-in-recurrent-metastatic-squamous-cell-carcinoma-of-the-head-and-neck-phase-ii-unicancer-trial-orl03
#11
Jerome Fayette, Joel Guigay, Christophe Le Tourneau, Marian Degardin, Frederic Peyrade, Eve-Marie Neidhardt, Marie-Paule Sablin, Caroline Even, Florence Orlandini, Béata Juzyna, Carine Bellera
Treatments are limited after platinum Cetuximab or anti-PD1 failure for patients with recurrent/metastatic head and neck squamous cell carcinoma. Cabazitaxel has increased overall survival in hormone-refractory metastatic prostate cancer after failure of Docetaxel. Our aim was to detect a signal of activity with Cabazitaxel in patients with head and neck cancer who had failed platinum-, Cetuximab- and taxanes-based chemotherapy. This multicenter phase II trial included progressive patients with an ECOG ≤2...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878208/hsp90-inhibition-enhances-cancer-immunotherapy-by-upregulating-interferon-response-genes
#12
Rina M Mbofung, Jodi A McKenzie, Shruti Malu, Min Zhang, Weiyi Peng, Chengwen Liu, Isere Kuiatse, Trang Tieu, Leila Williams, Seram Devi, Emily Ashkin, Chunyu Xu, Lu Huang, Minying Zhang, Amjad H Talukder, Satyendra C Tripathi, Hiep Khong, Nikunj Satani, Florian L Muller, Jason Roszik, Timothy Heffernan, James P Allison, Gregory Lizee, Sam M Hanash, David Proia, Rodabe Amaria, R Eric Davis, Patrick Hwu
T-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28873125/neurological-complications-associated-with-anti-programmed-death-1-pd-1-antibodies
#13
Justin C Kao, Bing Liao, Svetomir N Markovic, Christopher J Klein, Elie Naddaf, Nathan P Staff, Teerin Liewluck, Julie E Hammack, Paola Sandroni, Heidi Finnes, Michelle L Mauermann
Importance: Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. Objective: To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. Design, Setting, and Participants: This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016...
September 5, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28871357/-immunotherapy-as-modern-tumor-treatment
#14
REVIEW
C Grüllich
BACKGROUND: The specific immune system is capable of preventing the development of tumor diseases and stimulation of cytotoxic T‑lymphocytes can repress existing tumors. The activation of T‑lymphocytes is influenced by a new class of antibody-based medication, the immune checkpoint inhibitors. METHODS: Review of the scientific background and the published clinical trials on the activity and approval of immune checkpoint inhibitors for various tumor diseases...
September 4, 2017: Der Radiologe
https://www.readbyqxmd.com/read/28870260/programmed-cell-death-ligand-1-cut-point-is-associated-with-reduced-disease-specific-survival-in-resected-pancreatic-ductal-adenocarcinoma
#15
Basile Tessier-Cloutier, Steve E Kalloger, Mohammad Al-Kandari, Katy Milne, Dongxia Gao, Brad H Nelson, Daniel J Renouf, Brandon S Sheffield, David F Schaeffer
BACKGROUND: Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC). METHODS: A tissue microarray (TMA) was constructed from cases of resected PDAC...
September 5, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28861116/enabling-a-genetically-informed-approach-to-cancer-medicine-evaluation-of-the-impact-of-comprehensive-tumor-sequencing
#16
Elizabeth J Davis, Douglas B Johnson
"The role of next-generation sequencing to determine appropriateness of anti-PD1/PD-L1 therapy needs further investigation, but has shown promise in predicting response and survival in melanoma and urothelial carcinoma."
May 2017: Personalized Medicine
https://www.readbyqxmd.com/read/28838649/brachytherapy-attains-abscopal-effects-when-combined-with-immunostimulatory-monoclonal-antibodies
#17
María E Rodriguez-Ruiz, Inmaculada Rodriguez, Benigno Barbes, Lina Mayorga, Alfonso Rodriguez Sanchez-Paulete, Mariano Ponz-Sarvise, José Luis Pérez-Gracia, Ignacio Melero
PURPOSE/OBJECTIVES: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on tumors at distant, nonirradiated sites. We have recently reported that external beam radiotherapy achieves abscopal effects when combined with antagonist anti-PD1 mAbs and agonist anti-CD137 (4-1BB) mAbs. The goal of this work is to study the abscopal effects of radiotherapy instigated by brachytherapy techniques...
August 21, 2017: Brachytherapy
https://www.readbyqxmd.com/read/28836129/enlighting-the-shadow-for-advanced-hepatocellular-carcinoma-immunotherapy-with-immune-checkpoint-inhibitors
#18
REVIEW
Berksoy Sahin
Hepatocellular carcinoma has still been one of the cancer with increasing incidence and highest mortality rate in the world. Although many new promising developments have been defined in hepatocarcinogenesis, with a short survival the treatment of patients with advanced hepatocellular carcinoma is an emerging issue. On the recent decade, only one anti-angiogenic agent sorafenib improved overall survival with costing a hardly manageable toxicity. Novel immunotherapeutic agents, especially immune checkpoint inhibitors are on the edge of more effective but less toxic treatments for these patients...
August 23, 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28834746/pdl1-signals-through-conserved-sequence-motifs-to-overcome-interferon-mediated-cytotoxicity
#19
Maria Gato-Cañas, Miren Zuazo, Hugo Arasanz, Maria Ibañez-Vea, Laura Lorenzo, Gonzalo Fernandez-Hinojal, Ruth Vera, Cristian Smerdou, Eva Martisova, Imanol Arozarena, Claudia Wellbrock, Diana Llopiz, Marta Ruiz, Pablo Sarobe, Karine Breckpot, Grazyna Kochan, David Escors
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway...
August 22, 2017: Cell Reports
https://www.readbyqxmd.com/read/28826697/-reirradiation-of-head-and-neck-cancers
#20
J Doyen, D Lam Cham Kee, L Krebs, J Guigay, O Dassonville, F Peyrade, G Poissonnet, E Saâda-Bouzid, A Sudaka, A Bozec, K Bénézery
Locoregional relapse in previously irradiated region for head and neck tumours is associated with a bad locoregional and distant prognosis. Reirradiation might be exclusive, or feasible in addition with surgery and/or chemotherapy, according to histopronostic factors. Data show that reirradiation is feasible with some severe toxicity due to the bad prognosis of this situation. Hyperfractionnated regimen with split course or normofractionnated regimen without split course are possible with similar efficacy. If tumour size is small, stereotactic ablative radiotherapy may be considered, and if the treatment centre has proton therapy, it could be proposed because of better organs at risk sparing...
August 18, 2017: Cancer Radiothérapie: Journal de la Société Française de Radiothérapie Oncologique
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