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.

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…The results from the present study, with immune cell-specific PD-L1 expression being an independent prognostic factor while its expression in tumour cells was not, are coherent with previous research 16 , 23-26 and demonstrate that PD-L1 expression in immune cells and tumour cells might carry different prognostic values and might be regulated by distinct mechanisms. Furthermore, although tumour cell-specific PD-L1 expression has been validated as a predictive marker for response to PD-1 or PD-L1 blockade in several cancers, 11 , 38 , 39 recent studies now suggest that PD-L1 expression in tumour-infiltrating myeloid and T cells also play a critical role in immunosuppression, 38 , 40-43 and should possibly be taken into account in assessment scoring for PD-1/PD-L1 blockade.…”

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs—Part B: Prostate and Bladder Tumours

“…The most frequently altered pathways in bladder cancer include the PI3K/AKT/mammalian target of rapamycin pathway [96,[119][120][121], the FGFR3/RAF/RAS pathway, the TP53/RB1 pathway, immune response checkpoint modulators [122,123], and chromatin-regulating and -remodelling genes [124][125][126]. In general, mutations along a given pathway are mutually exclusive.…”

Expansion of tumor infiltrating lymphocytes (TIL) from bladder cancer

“…5 In clinically advanced medications targeting the PD1/PDL1 pathway have demonstrated an improvement in overall survival of 4 – 8 months with some durable responses but with only a 20% response rate overall. 6 Unfortunately, this still leaves median overall survival (OS) slightly over one year in patients with metastatic disease and even worse for non-responders. 7,8 …”