BMS_PD-L1_onco : Assessment of the PD-L1 Protein as a Biomarker in Oncology and Hematology
Condition: Diffuse Large B-cell Lymphoma; Hodgkin Lymphoma; Metastatic Breastcancer; Non-small Cell Lung Cancer
MeSH terms: Lymphoma; Carcinoma, Non-Small-Cell Lung; Lymphoma, B-Cell; Hodgkin Disease; Lymphoma, Large B-Cell, Diffuse; Breast Neoplasms
Study type: Observational

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
    

Observational model: Case-Crossover
Time perspective: Prospective
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
      
Biospecimen description: 
      Biomedical research on total blood at diagnosis.
    
Keywords: diffuse large B-cell lymphoma (DLBCL); Hodgkin lymphoma; metastatic breast cancer.; non-small cell lung cancer