Diffuse Large B-cell Lymphoma, Hodgkin Lymphoma, Metastatic Breastcancer, Non-small Cell Lung Cancer
Conditions
Keywords
diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma, metastatic breast cancer., non-small cell lung cancer
Brief summary
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).
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
Interventions
None listed
Sponsors
Roche Pharma AG
National Research Agency, France
Rennes University Hospital
Study design
Observational model
CASE_CROSSOVER
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
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 : \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 monocytes, B and T lymphocytes in all cohorts | 4 years | Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts |
| Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013) | 4 years | Development of an ELISPOT technique to detect soluble PD-L1 in the supernatants of sorted primary cells (subpart ended mid 2013) |
| 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 tumor cells by multiparameter flow cytometry and Veridex® in DLBCL and metastatic breast cancer, and bone marrow tumor cells by flow cytometry in DLBCL |
| 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 | Correlation between the PD-L1 expression \*) in the plasma, \*\*) in the tumor and \*\*\*) in the bronchoalveolar liquid 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 response to treatment according to soluble PD-L1 expression in 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 | 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 techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1 | 4 years | Evaluation of the techniques (by immunomagnetic or cell-sorting) used to separate circulating tumor cells expressing PD-L1 |
Countries
France
Outcome results
None listed