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
