Molecular Biomarkers of Response to PD-1/ PD-L1 Immune Checkpoint Blockade in Advanced Bladder Cancer1

Abstract

Background: The activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response. Objective: To conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease. Methods: A search of the literature was performed using Embase (1947-January 2019), Medline (1946-January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR). Results: Using the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8 + T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFN␥ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor ␤ (TGF␤) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings.

PD-L1 Expression in Muscle Invasive Urothelial Carcinomas as Assessed via Immunohistochemistry: Correlations with Specific Clinical and Pathological Features, with Emphasis on Prognosis after Radical Cystectomy

“…PD-L1 expression as determined by immunohistochemistry (IHC) was the first clinically validated predictive factor of UC treatment outcome to be translated into clinical practice, and PD-L1 is today the most extensively studied biomarker in UCs [ 10 ]. Nevertheless, data regarding its potential prognostic and/or predictive value in UCs are conflicting among reports from different trials [ 8 , 12 , 13 , 14 ]. The inherent morphological and genomic heterogeneity observed in UC cases may influence PD-L1-positive expression rates.…”

Cancer Stem Cells—Key Players in Tumor Relapse

“…The key role of EMT-related cell plasticity in immunosuppression and immunotherapy resistance has been highlighted in different tumor types [207], its prognostic value has been analyzed for gliomas [208], and TGFβ expression has been associated with poor prognosis in advanced bladder cancer, with a possible intrinsic resistance to PD-1 blockade [209]. Giving these observations, CSCs seem to represent an ideal target for ICIs.…”

Improving Anti-PD-1/PD-L1 Therapy for Localized Bladder Cancer

“…Despite high PD-L1 expression by IHC, many BC patients do not respond to PD-1/PD-L1 inhibitors, so more accurate biomarkers are needed. Thus far, three systematic reviews reported on the use biomarkers in advanced BC and concluded that none of the current biomarkers were of sufficient quality for use in clinical practice [ 27 , 28 , 29 ].…”

“…Overall, PD-1/PD-L1 blockade for localized BC is encouraging, but interpretation of data is hampered by small sample size, a lack of independent validation and patient-derived pre-clinical models for hypothesis testing [ 27 ]. Moreover, based on relatively low overall response rates of Keynote-057, PURE-01 and ABACUS, there is clearly room for improvement.…”