Evaluation of PD-L1 Expression and Immune Infiltration in High-risk Non Muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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Non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence (60 to 70%) and progression (20 to 30%) to muscle-invasive bladder cancer (MIBC). The local immunotherapy (intra-vesical Bacillus Calmette-Guerin (BCG) following transurethral resection of the bladder tumor (TURBT)) reduces significantly the risk of recurrence and progression as compared to observation or to intra-vesical chemotherapy. Systemic immunotherapy with programmed death ligand-1 (PD-L1) or Programmed cell Death 1 (PD1) inhibitors has shown major efficacy in the treatment of patients with advanced/metastatic urothelial carcinoma who have progressed on platinum-based regimens of chemotherapy, or even in front line setting. In the field of NMIBC, immunotherapy using PD-L1 or PD1 inhibitors is under investigation but the frequency of PD-L1 expression has rarely been precisely described in the different subtypes. The aim of this retrospective study is to investigate the expression of PD-L1 by different types of NMIBC. The secondary objective is to characterize the immune contexture of NMIBC.

Detailed Description
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Non-muscle-invasive bladder cancer (NMIBC) has a high rate of recurrence (60 to 70%) and progression (20 to 30%) to muscle-invasive bladder cancer (MIBC). The local immunotherapy (intra-vesical Bacillus Calmette-Guerin (BCG) following transurethral resection of the bladder tumor (TURBT)) reduces significantly the risk of recurrence and progression as compared to observation or to intra-vesical chemotherapy. Systemic immunotherapy with programmed death ligand-1 (PD-L1) or Programmed cell Death 1 (PD1) inhibitors has shown major efficacy in the treatment of patients with advanced/metastatic urothelial carcinoma who have progressed on platinum-based regimens of chemotherapy, or even in front line setting. In the field of NMIBC, immunotherapy using PD-L1 or PD1 inhibitors is under investigation but the frequency of PD-L1 expression has rarely been precisely described in the different subtypes. The aim of this retrospective study is to investigate the expression of PD-L1 by different types of NMIBC. The secondary objective is to characterize the immune contexture of NMIBC. The immunological contexture of NMIBC in comparison with normal bladder tissue and invasive bladder cancer will be deciphered. The objective is to determine immune signatures associated with response or relapse/progression, with and without immune treatments in NMIBC.

Official Title
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Evaluation of PD-L1 Expression and Immune Infiltration in High-risk Non Muscle Invasive Bladder Cancer

Conditions
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Bladder Cancer

Intervention / Treatment
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* Biological: Samples of bladder tissue


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically documented normal bladder, NMIBC (Ta, T1, CIS) or MIBC stored in the tissue bank. Samples collected from 2007 to 2011. 3 years follow-up is mandatory to assess the frequency of recurrences and progressions. Exclusion Criteria: History of autoimmune disease Active tuberculosis Prior treatment with CD137 agonists, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with histologically documented normal bladder<br> | Biological: Samples of bladder tissue<br>* Samples of bladder tissue collected between 2007 and 2011.<br>|
| Patients with histologically documented Non Muscle Invasive Bladder Cancer<br> | Biological: Samples of bladder tissue<br>* Samples of bladder tissue collected between 2007 and 2011.<br>|
| Patients with histologically documented Muscle Invasive Bladder Cancer<br> | Biological: Samples of bladder tissue<br>* Samples of bladder tissue collected between 2007 and 2011.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PD-L1 status (positive or negative) of the tumor and tumor associated immune cells. | PD-L1 status will be considered positive if more than 25% of tumor cells exhibit membrane staining or immune cells present (ICP) >1% and immune cells (IC)+ >25% or ICP=1% and IC+ = 100%. PD-L1 status will be considered negative if none of the criteria for PD-L1 positive status are met. | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Descriptive analysis of the differential expression of all the following immune biomarkers in normal bladder tissue, NMIBC (Non Muscle Invasive Bladder Cancer) and MIBC (Muscle Invasive Bladder Cancer). | Descriptive statistics will be performed from clinical characteristics as mean values for categorical variables, or medians (range) for non-normal continuous variables. | Day 1 | 
| Association of immune profile with recurrence and progression rates | Association between all variables will be analysed with t-test, Mann Whitney or ANOVA multiple comparison test. Correlation analysis will be performed with χ2 and Fischer exact test. Results will be considered significant if the p-value is <0.05. | Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non Muscle Invasive Bladder Cancer, Bacillus Calmette-Guerin, Programmed cell Death-Ligand protein 1, Programmed cell Death 1, Muscle Invasive Bladder Cancer