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MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
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MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
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Journal Article
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
2014
Overview
The results of a clinical phase I study in metastatic urothelial bladder cancer treated with the MPDL3280A antibody show that expression of PD-L1 on tumour-infiltrating immune cells is relevant for the therapeutic response.
MPDL3280A efficacy in metastatic bladder cancer
Thomas Powles
et al
. report the results of a clinical phase I study in metastatic urothelial bladder cancer treated with the anti-PDL1 antibody MPDL3280A. The transmembrane protein PD-L1 (programmed death-ligand 1) is upregulated in many different types of cancer and protocols targeting its interactions have shown promise in pre-clinical studies. This paper shows MPDL3280A to be particularly active against tumours with PD-L1-positive tumour-infiltrating immune cells. In addition, PD-L1-negative patients achieved a 11% response, which could be of significance given the historical rates of response in this type of cancer.
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
1
,
2
. One hallmark of UBC is the presence of high rates of somatic mutations
3
,
4
,
5
. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens
6
. 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
7
,
8
. 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)
9
. 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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
