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Exosomes and Immunotherapy in Non-Hodgkin B-cell Lymphomas (ExoReBLy)

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ClinicalTrials.gov Identifier: NCT03985696
Recruitment Status : Recruiting
First Posted : June 14, 2019
Last Update Posted : July 8, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Limoges

Brief Summary:
Diffuse large B-cell lymphomas (DLBCL) are highly aggressive and heterogeneous B-cell lymphoma that would imminently be fatal without treatment. Monoclonal anti-CD20 antibody, rituximab, in combination of CHOP chemotherapy (R-CHOP) is widely used with favourable results. Although more than half of patients achieve long-term remission, many are not cured with this immunotherapy. Suboptimal response and/or resistance to rituximab have remained a challenge in the therapy of DLBCL but also of all B-NHL. Exosomes are microvesicles released from tumor B cells that are found in plasma of patients with B-NHL. Exosomes carry therapeutic targets (as CD20, PDL-1) and could act as "decoy-receptors" for immunotherapy. Our objective is to precise, in aggressive B-NHL, the role of exosomes in immunotherapy escape.

Condition or disease Intervention/treatment Phase
Lymphoma, B-cell, Aggressive Non-Hodgkin (B-NHL) Other: blood sample Not Applicable

Detailed Description:

Diffuse large B-cell lymphomas (DLBCL) are highly aggressive and heterogeneous B-cell lymphoma that would imminently be fatal without treatment. Monoclonal anti-CD20 antibody, rituximab, in combination of CHOP chemotherapy (R-CHOP) is widely used with favourable results. Although more than half of patients achieve long-term remission, many are not cured with this immunotherapy. Decreased CD20 expression has been postulated to be one of the most important contributing to rituximab resistance. Moreover, R-CHOP therapies are sometimes ineffective, and new treatment strategies based notably on host immune responses modulation are being explored. Among them, programmed cell death ligand 1 (PD-L1) protein was identified as a potent predicting biomarker in DLBCL. Exosomes are small membrane vesicles secreted by several cell types during exocytic fusion of multivesicular bodies with the plasma membrane. Many cancer cells have been shown to secrete exosomes in greater amounts than normal cells. Exosome secretion may contribute to drug resistance. Indeed, exosome release from B-cell Non-Hodgkin Lymphoma (B-NHL), by the expression of CD20, has been suggest to act as decoy targets upon rituximab exposure, allowing lymphoma cells to escape from humoral immunotherapy. Finally, as exosome composition seems to be cell and tissue specific, they are highly suitable to serve as diagnostic markers.

Our hypothesis is that high expression of the immunotherapeutic targets (CD20, PD-L1) on exosomes derived from aggressive or resistant B-NHL may allow tumor cells to escape therapeutic antibodies, and thus contribute in vivo to therapeutic resistance. For this objective, we will used exosomes derived from DLBCL human cells and exosomes isolated from plasma of DLBCL patients. We will analyze, on these microvesicles, CD20 and PDL-1 expression in function of DLBCL sub-types and outcome of patients. Moreover, exosome capacity to interfere with immunotherapy will be also studied from in vitro and in vivo (xenografts) models.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Exosomes and Resistance to Immunotherapy in Aggressive Non-Hodgkin B-cell Lymphomas (B-NHL)
Actual Study Start Date : July 2, 2019
Estimated Primary Completion Date : July 2, 2025
Estimated Study Completion Date : July 2, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: patients with DLBCL Other: blood sample
1 blood volume (5-7 ml EDTA)

Active Comparator: Healthy volunteers Other: blood sample
1 blood volume (5-7 ml EDTA)




Primary Outcome Measures :
  1. Quantification of CD20 and PDL-1 in exosomes purified from cell cultures of DLBCL human cell lines and from Healthy volunteers [ Time Frame: Month 36 ]
    From D0 until the end of the inclusion period (36 months)


Secondary Outcome Measures :
  1. Evaluation if peripheral exosomes can be used as novel diagnostic biomarkers in DLBCL [ Time Frame: Month 36 ]
    To analyze the prognostic value of exosomal markers on therapeutic response and patient outcome, each patient included in the study at diagnostic (D0) will be followed up until 36 months after inclusion.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria :

  • patients over 18 years old with DLBCL at diagnostic or relapsed patients after R-CHOP therapy.
  • Healthy volunteers over 18 years old

Exclusion Criteria:

  • other B cell diseases

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03985696


Contacts
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Contact: Julie ABRAHAM, Dr +33 (0) 555 056 651 julie.abraham@chu-limoges.fr
Contact: Danielle TROUTAUD, Pr danielle.troutaud@unilim.fr

Locations
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France
University Hospital Limoges Recruiting
Limoges, France, 87042
Contact: JULIE ABRAHAM, PH       julie.abraham@chu-limoges.fr   
Sponsors and Collaborators
University Hospital, Limoges

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Responsible Party: University Hospital, Limoges
ClinicalTrials.gov Identifier: NCT03985696     History of Changes
Other Study ID Numbers: 87RI18_0025 (ExoReBLy)
First Posted: June 14, 2019    Key Record Dates
Last Update Posted: July 8, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital, Limoges:
B cells
exosomes
immunotherapy
Lymphomas
DLBCL

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Aggression
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Behavioral Symptoms
Immunologic Factors
Physiological Effects of Drugs