Prognostic significance of pre- and post-treatment PD-L1 expression in patients with primary high-grade non-muscle-invasive bladder cancer treated with BCG immunotherapy

Aydın, Ahmet; Baydar, Dilek Ertoy; Hazir, Berk; Babaoğlu, Berrin; Bilen, Cenk Yücel

doi:10.1007/s00345-019-03065-2

Cited by 22 publications

(24 citation statements)

References 32 publications

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“…A combination of the toll like receptor (TLR) activating BCG with blocking of PD-L1/PD-1 signaling might additionally increase the efficiency of the treatment [46] . However, there are conflicting data regarding the association of cancer PD-L1 expression with response to classical BCG treatment [47,48]. Recent data indicate that colocalization of PD-L1 with CD8 might be an indicator for resistance against BCG therapy [48].…”

Section: Therapeutic Potentialmentioning

confidence: 99%

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

et al. 2021

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Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

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Section: Therapeutic Potentialmentioning

confidence: 99%

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

et al. 2021

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“…Only relevant five articles were identified in the literature to date. The characteristic and primary findings of available studies are summarised in Table 1 [6][7][8][9][10]. In an analysis of 22 patients with high-risk NMIBC, Martínez et al [6] found that pre-treatment PD-L1 expression did not differ significantly between patients classified as BCG 'responders' and 'non-responders', defined as patients without a recurrence or progression for ≥30 months after BCG treatment initiation.…”

Section: Resultsmentioning

confidence: 99%

“…PD-L1 expression, evaluated after BCG treatment, did not change significantly. Aydin et al [9] analysed the pre-treatment PD-L1 expression in 117 patients with high-grade NMIBC. The authors found a significant association between positive PD-L1 expression on tumour infiltrating ICs and refractory recurrence (defined according to criteria specified in European Association of Urology [EAU] guidelines).…”

Section: Resultsmentioning

confidence: 99%

“…Although some studies have shown a positive correlation between increased PD-L1 expression and BCG unresponsiveness, results could be biased because of the small patient cohorts [8,10]. Studies with a large number of participants provided contradictory conclusions and suggested that evaluating PD-L1 expression could not be used for the prediction of BCG response [7,9]. The high level of inconsistency among the available studies may result from fact that PD-L1 expression was evaluated by IHC and multiple assays with different antibody clones were used.…”

Section: Discussionmentioning

confidence: 99%

“…The results indicated that high PD-L1 mRNA expression was associated with significantly improved RFS, PFS and cancerspecific survival [11]. Among the included studies, only Aydin et al [9] provided data for RFS and PFS, and positive PD-L1 expression was not correlated with any survival parameter. This raises doubts as to whether increased PD-L1 expression reflects poor overall prognosis in patients with NMIBC treated with BCG.…”

Section: Discussionmentioning

confidence: 99%

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The prognostic value of programmed cell death protein ligand 1 in patients with non-muscle-invasive bladder cancer treated with bacille Calmette–Guérin immunotherapy: Current status

Nowak

Krajewski

Poterek

et al. 2020

Arab Journal of Urology

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Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

Hannouneh,

Hijazi,

Alsaleem

et al. 2023

Cancer Medicine

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BackgroundHigh‐risk non‐muscle‐invasive bladder cancer (HR‐NMIBC) presents a challenge to many physicians due to its ability to resist Bacillus Calmette–Guérin (BCG) intravesical therapy and the substantial rate of progression into muscle‐invasive bladder cancer (MIBC). Patients who are BCG‐unresponsive have worse prognosis and thus require further management including radical cystectomy (RC), which significantly impacts quality of life. Moreover, the ongoing worldwide shortage of BCG warrants the need for policies that prioritize drug use and utilize alternative treatment strategies. Hence, there is a significant unmet need for bladder preserving therapy in this subset of patients.MethodsTo address this issue, we searched the relevant literature in PUBMED for articles published from 2019 through May of 2023 using appropriate keywords. All clinical trials of patients with HR‐NMIBC treated with immune‐related agents were retrieved from clinicaltrials.gov.Findings and Future PerspectivesExploratory treatments for BCG‐Unresponsive HR‐NMIBC included immune checkpoint inhibitors (ICI), oncolytic viral therapy, cytokine agonists, and other immunomodulators targeting TLR, EpCaM, FGFR, MetAP2, and IDO1. Some combination therapies have been found to work synergistically and are preferred therapeutically over monotherapy. Three drugs—pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec‐vncg—have been FDA approved for the treatment of BCG‐unresponsive NMIBC in patients who are ineligible for or decline RC. However, all explored treatment options tend to postpone RC rather than provide long‐term disease control. Additional combination strategies need to be studied to enhance the effects of immunotherapy. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR‐NMIBC is essential for the discovery of new targets and the development of effective treatments.

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Prognostic significance of pre- and post-treatment PD-L1 expression in patients with primary high-grade non-muscle-invasive bladder cancer treated with BCG immunotherapy

Cited by 22 publications

References 32 publications

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

The prognostic value of programmed cell death protein ligand 1 in patients with non-muscle-invasive bladder cancer treated with bacille Calmette–Guérin immunotherapy: Current status

Novel immunotherapeutic options for BCG‐unresponsive high‐risk non‐muscle‐invasive bladder cancer

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