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  • 1
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    MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-11-28
    Description: There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Powles, Thomas -- Eder, Joseph Paul -- Fine, Gregg D -- Braiteh, Fadi S -- Loriot, Yohann -- Cruz, Cristina -- Bellmunt, Joaquim -- Burris, Howard A -- Petrylak, Daniel P -- Teng, Siew-leng -- Shen, Xiaodong -- Boyd, Zachary -- Hegde, Priti S -- Chen, Daniel S -- Vogelzang, Nicholas J -- England -- Nature. 2014 Nov 27;515(7528):558-62. doi: 10.1038/nature13904.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Barts Cancer Institute, Queen Mary University of London, Barts Experimental Cancer Medicine Centre, London EC1M 6BQ, UK. ; Yale Cancer Center, 333 Cedar Street, WWW211, New Haven, Connecticut 06520, USA. ; Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA. ; Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA. ; Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. ; Vall d'Hebron Institute of Oncology (VHIO) and Vall d'Hebron University Hospital. Passeig Vall d'Hebron, 119-129, 08035, Barcelona, Spain. ; Bladder Cancer Center, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, Tennessee 37203, USA. ; University of Nevada School of Medicine and US Oncology/Comprehensive Cancer Centers of Nevada, 3730 S. Eastern Avenue, Las Vegas, Nevada 89169, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428503" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/adverse effects/*therapeutic use ; Antigens, CD274/metabolism ; Female ; Humans ; *Immunotherapy ; Male ; Middle Aged ; Treatment Outcome ; Urinary Bladder Neoplasms/*therapy
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-11-28
    Description: The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herbst, Roy S -- Soria, Jean-Charles -- Kowanetz, Marcin -- Fine, Gregg D -- Hamid, Omid -- Gordon, Michael S -- Sosman, Jeffery A -- McDermott, David F -- Powderly, John D -- Gettinger, Scott N -- Kohrt, Holbrook E K -- Horn, Leora -- Lawrence, Donald P -- Rost, Sandra -- Leabman, Maya -- Xiao, Yuanyuan -- Mokatrin, Ahmad -- Koeppen, Hartmut -- Hegde, Priti S -- Mellman, Ira -- Chen, Daniel S -- Hodi, F Stephen -- 1R01CA155196/CA/NCI NIH HHS/ -- P30 CA 016359/CA/NCI NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- R01 CA155196/CA/NCI NIH HHS/ -- England -- Nature. 2014 Nov 27;515(7528):563-7. doi: 10.1038/nature14011.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA. ; Gustave Roussy South-Paris University, 114 Rue Edouard Vaillant, 94805 Villefuij, Cedex, France. ; Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; The Angeles Clinic and Research Institute, 11818 Wilshire Blvd, Los Angeles, California 90025, USA. ; Pinnacle Oncology Hematology, 9055 E Del Camino Dr 100, Scottsdale, Arizona 85258, USA. ; Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, Tennessee 37212, USA. ; Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Shapiro 9, Boston, Massachusetts 02215, USA. ; Carolina BioOncology Institute, 9801 W. Kincey Ave, Suite 145, Huntersville, North Carolina 28078, USA. ; Stanford University, CCSR Bldg Room 1110, Stanford, California 94305, USA. ; Vanderbilt-Ingram Cancer Center, 1301 Medical Center Dr, Suite 1710, Nashville, Tennessee 37212, USA. ; Massachusetts General Hospital, 55 Fruit Street, YAW 9E, Boston, Massachusetts 02114, USA. ; Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428504" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/adverse effects/*therapeutic use ; Antigens, CD274/*antagonists & inhibitors/metabolism ; Biomarkers/blood ; CTLA-4 Antigen/metabolism ; Chemokine CX3CL1/metabolism ; Clinical Protocols ; Disease-Free Survival ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; *Immunotherapy/adverse effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Middle Aged ; Neoplasms/diagnosis/*therapy ; Treatment Outcome ; Young Adult
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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