BMS_PD-L1_onco : Assessment of the PD-L1 Protein as a Biomarker in Oncology and Hematology (BMS_PD-L1)

Diffuse large B-cell lymphomas (DLBCLs) represent 25 to 30% of adult non-Hodgkin lymphomas in western countries. DLBCLs are aggressive cancer but potentially curable with multi-agent chemotherapy. Whereas R-CHOP regimen has led to a marked improvement in survival, this disease remains a biologically heterogeneous entity. New therapeutic strategies are required including identification of patients' subgroups with different prognostic.

This project is based on BMS_LyTrans and Goelams 075 clinical trial. A study of whole blood transcriptome in 75 DLBCL patients and in 87 controls showed that PD-L1 (CD274) gene was overexpressed in DLBCL patients. Preliminary results demonstrated that PD-L1 is detected in plasma of DLBCL patients with a significantly higher concentration than in controls. This protein was selected as a potential biomarker because of its established role in anti-tumoral immunity. Interaction between PD-L1 and its receptor PD-1 is known to inhibit activation of immune responses by inducing T-lymphocytes anergy and/or apoptosis. Moreover, a direct involvement of PD-L1 in the protection of cancer cells from lysis by activated T lymphocytes has been demonstrated. PD-L1 expression has been described in several solid tumours, including ovary cancer, breast cancer, colon cancer, renal cell carcinoma, non-small cell lung carcinoma and in hematological malignancies such as T-NHL, MM and Hodgkin's lymphoma. Furthermore the expression of PD-L1 by tumour cells is associated with poor prognosis. The blockade of PD-L1/PD-1 axis may represent a novel therapeutic approach in aggressive cancers. These first results incite to identify the cells releasing soluble PD-L1 and to investigate its role in the anti-tumoral immunity in DLBCL patients.

The aim of this study is to identify cells producing soluble PD-L1 in DLBCL patients at diagnosis in comparison to others tumours known to express PD-L1 (metastatic breast cancer, Hodgkin's lymphoma, non-small cell lung cancer).

Study Overview

• Status: Completed
• Conditions: Hodgkin Lymphoma; Non-small Cell Lung Cancer; Diffuse Large B-cell Lymphoma; Metastatic Breastcancer

Detailed Description

Secondary purposes are :

• To confirm the presence of plasma soluble form of PD-L1 in others malignancies
• To study surface expression of PD-L1 on circulating tumour cells with multiparameter fow cytometry and Veridex® technology in DLBCL and metastatic breast cancer patients
• To study surface expression of PD-L1 on circulating endothelial cells in DLBCL, Hodgkin lymphoma and metastatic breast cancer patients (subpart ended in late 2012)
• To study surface expression of PD-L1 on different types of leukocytes (monocytes, B and T lymphocytes)
• To separate circulating tumour cells expressing PD-L1 by immunomagnetic or Cell-sorting method
• To develop ELISPOT technique to study the release of soluble PD-L1 in culture supernatants of selected cells (subpart ended mid 2013)
• to evaluate the correlation between the expression of PD-L1 in the plasma and *) the expression of PD-L1 in the tumor, **) the expression of PD-L1 and other molecules in the bronchoalveolar liquid (whenever available from routine) in non-small cell lung cancer
• to evaluate the response to treatment according to plasma PD-L1 expression in non-small cell lung cancer
• to evaluate the susceptibility to develop a disease according to the single nucleotide polymorphisms of the PD-L1 gene in DLBCL and non-small cell lung cancer
• Constitution of the different cohorts and collection of samples Main cohort : de novo DLBCL at diagnosis Secondary cohorts: Hodgkin's lymphoma, metastatic breast cancer, non small cell lung cancer Control cohorts : healthy volunteers (blood donors), patients with immune thrombocytopenia (ITP)
• Quantification of plasma soluble PD-L1 in the different cohorts

• Study Type: Observational
• Enrollment (Actual): 105

Contacts and Locations

Study Locations

• France
  • Marseille, France, 13000
    • Institut Paoli Calmette
  • Montpellier, France, 34000
    • Montpellier University Hospital
  • Brittanny
    • Rennes, Brittanny, France, 35000
      • Rennes EFS
    • Rennes, Brittanny, France, 35000
      • Rennes University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Number of DLBCL patients : 40 Number of non-small cell lung cancer patients : 100 Number of Hodgkin patients : 20 Number of metastatic breast cancer patients : 20 Number of healthy volunteers : 140 Number of patients with immune thrombocytopenia (ITP) : 5

Description

Inclusion Criteria:

General inclusion criteria :

• Age ≥ 18 years and ≤ 75 years,
• Life expectancy more than 4 months
• Signed informed consent obtained
• Social security affiliation is mandatory
• Non previously treated (even by corticotherapy),
• HIV negative, HBs negative, HCV negative

Inclusion criteria for DLBCL patients :

• A biopsy proven diagnosis of de novo DLBCL according to the current WHO criteria,
• Immunohistochemistry for GCB/nonGC classification according to Hans' algorithm
• Patients with advanced-stage disease defined as Ann Arbor stages III or IV, or stages I or II with bulky disease (>7cm)

Inclusion criteria for non-small cell lung cancer patients :

• A biopsy proven diagnosis of de novo non-small cell lung cancer (all stages) according to the current WHO criteria

Inclusion criteria for Hodgkin's lymphoma patients :

• A biopsy proven diagnosis of Hodgkin's lymphoma according to the current WHO criteria

Inclusion criteria for metastatic breast cancer or with lymph node involvement :

• A biopsy proven diagnosis infiltrating lobular or ductal breast carcinoma
• with lymph node involvement or metastasis

Inclusion criteria for patients with immune thrombocytopenia (ITP) :

• Primary ITP was defined by the IWG as a platelet count less than 100 G/L in the absence of other causes or disorders that may be associated with thrombocytopenia.
• Bone marrow examination excluding a central aetiology of thrombocytopenia

Inclusion criteria for healthy volunteers :

- Inclusion criteria for blood donation according to the Etablissement Français du Sang (EFS) criteria

Exclusion Criteria:

General non-inclusion criteria :

• Age < 18 years et > 75 years,
• Pregnant women,
• Person legally involved in a case
• No social security affiliation
• Signed informed consent not obtained,
• Preliminary treatment (even corticoid treatment).
• HIV positive, HBs positive, HCV positive

Non-inclusion criteria for DLBCL patients :

• Lymphoma other than DLBCL,
• Transformation of a low grade lymphoma to a high grade lymphoma (DLBCL),
• Extranodal marginal zone lymphoma of MALT lymphoma,
• Post-transplant lymphoproliferative disorders,
• Lymphoblastic lymphoma,
• Burkitt's lymphoma,
• Carcinoma or history of carcinoma except in situ cervical carcinoma.

Non-inclusion criteria for non-small cell lung cancer patients : None

Non-inclusion criteria for Hodgkin patients :

- Non Hodgkin's lymphoma

Non-inclusion criteria for metastatic breast cancer or with lymph node involvement :

• Carcinoma other than infiltrating lobular or ductal breast carcinoma
• Chemotherapy in 30 days preceding the inclusion
• Hormonotherapy in 7 days preceding the inclusion
• Carcinoma or history of carcinoma except in situ cervical carcinoma.
• Hemoglobin level < 10g/dl

Non-inclusion criteria for patients with immune thrombocytopenia (ITP) :

- Central aetiology of the thrombocytopenia

Non-inclusion criteria for healthy volunteers :

- Exclusion criteria for blood donation according to the Etablissement Français du Sang (EFS) criteria

Study Plan

How is the study designed?

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort
healthy volunteers
DLBCL (diffuse large B-cell lymphoma)
Hodgkin's lymphoma
metastatic breast cancer; metastatic breast cancer or with lymph node involvement
immune thrombocytopenia (ITP)
non-small cell lung cancer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Description of one or several blood cell types producing soluble PD-L1 in DLBCL, metastatic breast cancer, Hodgkin's lymphoma and non-small cell lung cancer	Description of one or several blood cell types producing soluble PD-L1 in DLBCL, metastatic breast cancer, Hodgkin's lymphoma and non-small cell lung cancer	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analysis of PD-L1 membrane protein expression on circulating tumor cells by multiparameter flow cytometry and Veridex® in DLBCL and metastatic breast cancer, and bone marrow tumor cells by flow cytometry in DLBCL	Analysis of PD-L1 membrane protein expression on circulating tumor cells by multiparameter flow cytometry and Veridex® in DLBCL and metastatic breast cancer, and bone marrow tumor cells by flow cytometry in DLBCL	4 years
Analysis of PD-L1 membrane protein expression on circulating endothelial cells with the Veridex® technology in DLBCL, Hodgkin's lymphoma and metastatic breast cancer (subpart ended in late 2012)	Analysis of PD-L1 membrane protein expression on circulating endothelial cells with the Veridex® technology in DLBCL, Hodgkin's lymphoma and metastatic breast cancer (subpart ended in late 2012)	4 years
Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts	Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts	4 years
Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013)	Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013)	4 years
Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1	Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1	4 years
Correlation between the PD-L1 expression *) in the plasma, **) in the tumor and ***) in the bronchoalveolar liquid in non-small cell lung cancer	Correlation between the PD-L1 expression *) in the plasma, **) in the tumor and ***) in the bronchoalveolar liquid in non-small cell lung cancer	4 years
Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer	Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer	4 years
Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer	Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer	4 years

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Collaborators: Roche Pharma AG; National Research Agency, France
• Investigators: Principal Investigator: Thierry Fest, MD, Rennes University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2012
• Primary Completion (Actual): October 2, 2017
• Study Completion (Actual): October 2, 2019

Study Registration Dates

• First Submitted: July 31, 2012
• First Submitted That Met QC Criteria: August 6, 2012
• First Posted (Estimate): August 9, 2012

Study Record Updates

• Last Update Posted (Actual): November 6, 2019
• Last Update Submitted That Met QC Criteria: November 5, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: non-small cell lung cancer; Hodgkin lymphoma; diffuse large B-cell lymphoma (DLBCL); metastatic breast cancer.
• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lung Diseases; Neoplasms by Site; Breast Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Hodgkin Disease
• Other Study ID Numbers: 2011-A01163-38; B111181-40 (Other Identifier: AFSSAPS); 11/32-821 (Other Identifier: CPP OUest V)