MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
- PMID: 25428503
- DOI: 10.1038/nature13904
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Abstract
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.
Comment in
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Bladder cancer: Could MPDL3280A offer a therapeutic breakthrough in metastatic bladder cancer?Nat Rev Urol. 2015 Feb;12(2):61. doi: 10.1038/nrurol.2014.344. Epub 2014 Dec 16. Nat Rev Urol. 2015. PMID: 25512206 No abstract available.
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Immunotherapy: PD-1-PD-L1 axis: efficient checkpoint blockade against cancer.Nat Rev Clin Oncol. 2015 Feb;12(2):63. doi: 10.1038/nrclinonc.2014.221. Epub 2014 Dec 23. Nat Rev Clin Oncol. 2015. PMID: 25533942 No abstract available.
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Words of wisdom. Re: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Eur Urol. 2015 May;67(5):975. doi: 10.1016/j.eururo.2014.12.065. Eur Urol. 2015. PMID: 25845961 No abstract available.
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Re: MPDL3280A (Anti-PD-L1) Treatment Leads to Clinical Activity in Metastatic Bladder Cancer.J Urol. 2015 Oct;194(4):956. doi: 10.1016/j.juro.2015.07.017. Epub 2015 Jul 10. J Urol. 2015. PMID: 26382775 No abstract available.
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