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Exosomes and Immunotherapy in Non-Hodgkin B-cell Lymphomas (ExoReBLy)
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Lymphoma, B-cell, Aggressive Non-Hodgkin (B-NHL) | Other: blood sample | Not Applicable |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 90 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 |
| 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)
|
- 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)
- 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.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
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
| Contact: Julie ABRAHAM, Dr | +33 (0) 555 056 651 | julie.abraham@chu-limoges.fr | |
| Contact: Danielle TROUTAUD, Pr | danielle.troutaud@unilim.fr |
| France | |
| University Hospital Limoges | Recruiting |
| Limoges, France, 87042 | |
| Contact: JULIE ABRAHAM, PH julie.abraham@chu-limoges.fr | |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | June 11, 2019 | ||||||||
| First Posted Date ICMJE | June 14, 2019 | ||||||||
| Last Update Posted Date | December 3, 2020 | ||||||||
| Actual Study Start Date ICMJE | July 2, 2019 | ||||||||
| Estimated Primary Completion Date | July 2, 2025 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
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)
|
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
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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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Exosomes and Immunotherapy in Non-Hodgkin B-cell Lymphomas | ||||||||
| Official Title ICMJE | Exosomes and Resistance to Immunotherapy in Aggressive Non-Hodgkin B-cell Lymphomas (B-NHL) | ||||||||
| 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. | ||||||||
| 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 ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Not Applicable | ||||||||
| Study Design ICMJE | Allocation: Non-Randomized Intervention Model: Parallel Assignment Masking: None (Open Label) Primary Purpose: Basic Science |
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| Condition ICMJE | Lymphoma, B-cell, Aggressive Non-Hodgkin (B-NHL) | ||||||||
| Intervention ICMJE | Other: blood sample
1 blood volume (5-7 ml EDTA)
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
90 | ||||||||
| Original Estimated Enrollment ICMJE |
75 | ||||||||
| Estimated Study Completion Date ICMJE | July 2, 2025 | ||||||||
| Estimated Primary Completion Date | July 2, 2025 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria :
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years and older (Adult, Older Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | France | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT03985696 | ||||||||
| Other Study ID Numbers ICMJE | 87RI18_0025 (ExoReBLy) | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | University Hospital, Limoges | ||||||||
| Study Sponsor ICMJE | University Hospital, Limoges | ||||||||
| Collaborators ICMJE | Not Provided | ||||||||
| Investigators ICMJE | Not Provided | ||||||||
| PRS Account | University Hospital, Limoges | ||||||||
| Verification Date | December 2020 | ||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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