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

tiistai 5. marraskuuta 2019 päivittänyt: Rennes University Hospital

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).

Tutkimuksen yleiskatsaus

Tila

Valmis

Ehdot

Yksityiskohtainen kuvaus

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

Opintotyyppi

Havainnollistava

Ilmoittautuminen (Todellinen)

105

Yhteystiedot ja paikat

Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.

Opiskelupaikat

Ranska
- - Marseille, Ranska, 13000
    - Institut Paoli Calmette
  - Montpellier, Ranska, 34000
    - Montpellier University Hospital
- Brittanny
  - Rennes, Brittanny, Ranska, 35000
    - Rennes EFS
  - Rennes, Brittanny, Ranska, 35000
    - Rennes University Hospital

Osallistumiskriteerit

Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.

Kelpoisuusvaatimukset

Opintokelpoiset iät

18 vuotta - 75 vuotta (Aikuinen, Vanhempi Aikuinen)

Hyväksyy terveitä vapaaehtoisia

Joo

Sukupuolet, jotka voivat opiskella

Kaikki

Näytteenottomenetelmä

Todennäköisyysnäyte

Tutkimusväestö

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

Kuvaus

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

Opintosuunnitelma

Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.

Miten tutkimus on suunniteltu?

Suunnittelun yksityiskohdat

Ryhmien/kohorttien lukumäärä

Kohortit ja interventiot

Ryhmä/Kohortti
terveitä vapaaehtoisia
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

Mitä tutkimuksessa mitataan?

Ensisijaiset tulostoimenpiteet

Tulosmittaus	Toimenpiteen kuvaus	Aikaikkuna
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 Aikaikkuna: 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	4 years

Toissijaiset tulostoimenpiteet

Tulosmittaus	Toimenpiteen kuvaus	Aikaikkuna
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 Aikaikkuna: 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	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) Aikaikkuna: 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)	4 years
Analysis of PD-L1 membrane protein expression on monocytes, B and T lymphocytes in all cohorts Aikaikkuna: 4 years	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) Aikaikkuna: 4 years	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 Aikaikkuna: 4 years	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 Aikaikkuna: 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	4 years
Evaluation of the response to treatment according to soluble PD-L1 expression in non-small cell lung cancer Aikaikkuna: 4 years	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 Aikaikkuna: 4 years	Evaluation of the susceptibility to develop a disease according to PD-L1 gene SNP in DLBCL and non-small cell lung cancer	4 years

Yhteistyökumppanit ja tutkijat

Täältä löydät tähän tutkimukseen osallistuvat ihmiset ja organisaatiot.

Sponsori

Rennes University Hospital

Yhteistyökumppanit

Roche Pharma AG

National Research Agency, France

Tutkijat

Päätutkija: Thierry Fest, MD, Rennes University Hospital

Opintojen ennätyspäivät

Nämä päivämäärät seuraavat ClinicalTrials.gov-sivustolle lähetettyjen tutkimustietueiden ja yhteenvetojen edistymistä. National Library of Medicine (NLM) tarkistaa tutkimustiedot ja raportoidut tulokset varmistaakseen, että ne täyttävät tietyt laadunvalvontastandardit, ennen kuin ne julkaistaan julkisella verkkosivustolla.

Opi tärkeimmät päivämäärät

Opiskelun aloitus (Todellinen)

Torstai 7. kesäkuuta 2012

Ensisijainen valmistuminen (Todellinen)

Maanantai 2. lokakuuta 2017

Opintojen valmistuminen (Todellinen)

Keskiviikko 2. lokakuuta 2019

Opintoihin ilmoittautumispäivät

Ensimmäinen lähetetty

Tiistai 31. heinäkuuta 2012

Ensimmäinen toimitettu, joka täytti QC-kriteerit

Maanantai 6. elokuuta 2012

Ensimmäinen Lähetetty (Arvio)

Torstai 9. elokuuta 2012

Tutkimustietojen päivitykset

Viimeisin päivitys julkaistu (Todellinen)

Keskiviikko 6. marraskuuta 2019

Viimeisin lähetetty päivitys, joka täytti QC-kriteerit

Tiistai 5. marraskuuta 2019

Viimeksi vahvistettu

Perjantai 1. marraskuuta 2019

Lisää tietoa

Tähän tutkimukseen liittyvät termit

Avainsanat

Muita asiaankuuluvia MeSH-ehtoja

Muut tutkimustunnusnumerot

2011-A01163-38
B111181-40 (Muu tunniste: AFSSAPS)
11/32-821 (Muu tunniste: CPP OUest V)

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