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Keith E Steele, Tze Heng Tan, René Korn, Karma Dacosta, Charles Brown, Michael Kuziora, Johannes Zimmermann, Brian Laffin, Moritz Widmaier, Lorenz Rognoni, Ruben Cardenes, Katrin Schneider, Anmarie Boutrin, Philip Martin, Jiping Zha, Tobias Wiestler
BACKGROUND: Immuno-oncology and cancer immunotherapies are areas of intense research. The numbers and locations of CD8+ tumor-infiltrating lymphocytes (TILs) are important measures of the immune response to cancer with prognostic, pharmacodynamic, and predictive potential. We describe the development, validation, and application of advanced image analysis methods to characterize multiple immunohistochemistry-derived CD8 parameters in clinical and nonclinical tumor tissues. METHODS: Commercial resection tumors from nine cancer types, and paired screening/on-drug biopsies of non-small-cell lung carcinoma (NSCLC) patients enrolled in a phase 1/2 clinical trial investigating the PD-L1 antibody therapy durvalumab (NCT01693562), were immunostained for CD8...
March 6, 2018: Journal for Immunotherapy of Cancer
Laura Mezquita, David Planchard
Immune checkpoint inhibitors (ICIs) are a key component of treating advanced cancer patients, principally antibodies against CTLA-4 and PD-1 or PD-L1. Durvalumab (MEDI4736) is a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1, which binds to PD-1 and CD80, but not to PD-L2. Single-agent durvalumab showed clinical efficacy and a manageable safety profile in advanced non-small-cell lung cancer, particularly the ≥25% PD-L1+ population. Durvalumab is under evaluation in early, locally advanced and advanced disease as monotherapy and combined with ICIs, targeted therapies, chemotherapy and radiotherapy...
February 2018: Future Oncology
Anshu Giri, Simrit S Walia, Ajeet Gajra
INTRODUCTION: Non-Small Cell Lung Cancer (NSCLC) is an aggressive malignancy with poor overall survival that accounts for up to 85% of lung cancer diagnoses. The use of immunotherapy in the form of checkpoint inhibition, to enhance the immune system's ability to attack malignant cells, has been a promising addition to treatment options in advanced NSCLC. RESULTS: Such therapeutic agents aimed at the Programmed Death 1 (PD-1) receptor or Programmed Death Ligand 1 (PD-L1) have revealed promising results against many types of cancer including NSCLC...
2016: Reviews on Recent Clinical Trials
Christophe Massard, Michael S Gordon, Sunil Sharma, Saeed Rafii, Zev A Wainberg, Jason Luke, Tyler J Curiel, Gerardo Colon-Otero, Omid Hamid, Rachel E Sanborn, Peter H O'Donnell, Alexandra Drakaki, Winston Tan, John F Kurland, Marlon C Rebelatto, Xiaoping Jin, John A Blake-Haskins, Ashok Gupta, Neil H Segal
PURPOSE: To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). METHODS: A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months...
September 10, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
David Planchard, Takashi Yokoi, Michael J McCleod, Jürgen R Fischer, Young-Chul Kim, Marc Ballas, Kelvin Shi, Jean-Charles Soria
Anti-programmed cell death-1 and anti-programmed cell death ligand-1 (PD-L1) monotherapies have shown promising clinical activity in advanced, refractory non-small-cell lung cancer (NSCLC), but antitumor activity appears to be greater in patients with PD-L1(+) tumors compared with patients harboring PD-L1(-) tumors. Combining the anti-PD-L1 antibody durvalumab and the anti-cytotoxic T-lymphocyte antigen 4 antibody tremelimumab offers the potential for antitumor activity in patients with advanced NSCLC, regardless of PD-L1 tumor status...
May 2016: Clinical Lung Cancer
D L Gibbons, L Q Chow, D-W Kim, S-W Kim, T Yeh, X Song, H Jiang, R Taylor, J Karakunnel, B Creelan
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
T Mok, P Schmid, O Arén, O Arrieta, M Gottfried, A R Jazieh, R Ramlau, K Timcheva, C Martin, S McIntosh
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
S Peters, S Antonia, S B Goldberg, J V Heymach, E S Kim, K Nakagawa, V Papadimitrakopoulou, P Mukhopadhyay, S McIntosh, N A Rizvi
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
S I Rothschild, A Zippelius, S Savic Prince, M Gonzalez, W Weder, A Xyrafas, C Rusterholz, M Pless
No abstract text is available yet for this article.
April 2016: Journal of Thoracic Oncology
Michael P Castro, Neal Goldstein
BACKGROUND: Mismatch repair deficiency (MMRD) is a common pathway of malignant transformation accounting for approximately 15-20 % of human carcinogensis. It has been postulated that MMRD increases tumor antigenicity and highlights a role for immunotherapeutic approach MMR-deficient cancers. This strategy was pursued in a patient with upper tract urothelial carcinoma, and the results are reported here. CASE PRESENTATION: Molecular profiling was performed using next generation DNA sequencing and (IHC) testing for MMR and PD-L1...
2015: Journal for Immunotherapy of Cancer
Eléonore de Guillebon, Pauline Roussille, Eric Frouin, David Tougeron
Human tumors tend to activate the immune system regulatory checkpoints as a means of escaping immunosurveillance. For instance, interaction between program death-1 (PD-1) and program death-ligand 1 (PD-L1) will lead the activated T cell to a state of anergy. PD-L1 is upregulated on a wide range of cancer cells. Anti-PD-1 and anti-PD-L1 monoclonal antibodies (mAbs), called immune checkpoint inhibitors (ICIs), have consequently been designed to restore T cell activity. Accumulating data are in favor of an association between PD-L1 expression in tumors and response to treatment...
August 15, 2015: World Journal of Gastrointestinal Oncology
Paolo A Ascierto, Francesco M Marincola, Michael B Atkins
Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma...
July 4, 2015: Journal of Translational Medicine
Joel Sunshine, Janis M Taube
Tumors may adopt normal physiologic checkpoints for immunomodulation leading to an imbalance between tumor growth and host surveillance. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. Nivolumab and pembrolizumab are the anti-PD-1 antibodies that are currently the furthest in clinical development, and anti-PD-L1 agents under investigation include MPDL3280A, MEDI4736, and BMS-936559. These agents have been used to treat advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other tumor types...
August 2015: Current Opinion in Pharmacology
Ramy Ibrahim, Ross Stewart, Aiman Shalabi
MEDI4736 is a human immunoglobulin (Ig) G1к monoclonal antibody that blocks programmed cell death ligand-1 (PD-L1) binding to its receptors, allowing T cells to recognize and kill tumor cells. Key attributes include high affinity and selectivity for PD-L1, sustained drug exposure for up to 1 year of dosing, and engineering of the antibody to prevent antibody-dependent cell-mediated cytotoxicity. No immunogenicity impacting on the pharmacokinetics/pharmacodynamics of MEDI4736 has been reported at the 10 mg/kg every 2 weeks dose selected for further clinical development...
June 2015: Seminars in Oncology
Ross Stewart, Michelle Morrow, Scott A Hammond, Kathy Mulgrew, Danielle Marcus, Edmund Poon, Amanda Watkins, Stefanie Mullins, Matthieu Chodorge, John Andrews, David Bannister, Emily Dick, Nicola Crawford, Julie Parmentier, Marat Alimzhanov, John S Babcook, Ian N Foltz, Andrew Buchanan, Vahe Bedian, Robert W Wilkinson, Matthew McCourt
Programmed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation...
September 2015: Cancer Immunology Research
Sylvia M Lee, Laura Q Chow
No abstract text is available yet for this article.
December 2014: Translational Lung Cancer Research
Christoph C Zielinski
A review and critical consideration of immunotherapeutical concepts in non-small cell lung cancer (NSCLC) is given. Nivolumab represents a promising option in various malignancies with more results exceeding treatment of metastatic malignant melanoma eagerly awaited.
December 2014: Translational Lung Cancer Research
Jing Lu, Linda Lee-Gabel, Michelle C Nadeau, Thomas M Ferencz, Scott A Soefje
Significant enthusiasm currently exists for new immunotherapeutic strategies: blocking the interaction between programmed death-1 receptor on T-cells and programmed death-ligand 1 on tumor cells to boost immune system stimulation to fight cancer. Immunomodulation with the antiprogrammed death-1/programmed death-ligand 1 monoclonal antibodies has shown to mediate tumor shrinkage and extend overall survival from several pivotal phase I/II studies in melanoma, renal cell carcinoma, and non-small cell lung cancer...
December 2015: Journal of Oncology Pharmacy Practice
Benjamin C Creelan
BACKGROUND: The immune checkpoint proteins, including the B7/CD28 receptor superfamily, have become increasingly important targets for pharmacologic blockade. Several classes of new agents have impressive clinical activity, and their eventual approval for treatment of lung cancer seems likely. METHODS: This article discusses the current development of these agents, including the CTLA-4, PD-1, and PD-L1 inhibitory pathways, killer immunoglobulin receptor (KIR ) inhibition, and other checkpoint proteins...
January 2014: Cancer Control: Journal of the Moffitt Cancer Center
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