Ignite Creation Date:
2024-05-06 @ 7:04 PM
Last Modification Date:
2024-10-26 @ 3:00 PM
Study NCT ID:
NCT05888701
Status:
RECRUITING
Last Update Posted:
2023-06-05
First Post:
2023-05-24
Brief Title:
Dont Eat me Signal in Hematological Malignancies CD24 as New Target to Improve Anti-cancer Immunity
Sponsor:
University of Milano Bicocca
Organization:
University of Milano Bicocca
Study Overview
Official Title:
Dont Eat me Signal in Hematological Malignancies CD24 as New Target to Improve Anti-cancer Immunity
Status:
RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Mantle-cell Lymphoma MCL is a B-cell non-Hodgkins lymphoma NHL with heterogeneous behaviorranging from indolent phenotype to highly aggressive and drug resistant cases with dismal prognosisDisease progression and drug resistance may be generated by Tumor Microenvironment TMEowing that M2-like immunosuppressive tumor associated macrophages TAM are pathologically functional in providing survival signals to MCL cells-and TME is known to help mask tumoral cells from host immune systemSimilarly Chronic Lymphocytic Leukemia CLL is a B-cell malignancy characterized by increased circulating number of mature B lymphocytes that eventually reside into bone marrow and lymphoid tissues as wellHigher number of circulating abnormal B cells is secondary to a balance between increased proliferation and decreased apoptosis activitiessustained by signals also deriving from TMEAs a matter of factTME harbors different cell compounds and monocyte-derived Nurse-like cells NLCs resemble the M2-like macrophage immunosuppressive profile and turned out to be an important component able to interact with CLL cells providing improvement of proliferation and survivalRecently cancer-expressed CD47 was found to be involved in tumor immune escape through interaction with Signal Regulatory Protein-α SIRP-α expressed by TAMbeing able to quench phagocytosis InterestinglyDont Eat Me signal DEMs blockade with anti-CD47 monoclonal Antibody mAb showed promising activity in pretreated NHLthrough increase of phagocytosis by TAMCD24 was also demonstrated to be involved in DEMs in solid cancerAs a matter of fact tumor-expressed CD24 promotes immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin10 Siglec-10expressed by TAM with immunosuppressive phenotype M2-likeIn a preclinical model of CD24 solid tumors ovarian and breast cancer the blockade of CD24-Siglec-10 interaction with anti-CD24 mAb showed improvement of TAM-associated phagocytosis in vitro and TAM-dependent reduction of tumor growth and increase of survival in vivoIt is worth mentioning that CD24 can be expressed in some phases of B-cell differentiation and both MCL and CLL derives from a B-cell precursor with upregulated CD24In this settingCD24 might play a critical role in the anti-phagocytic signal since MCL and CLL represents a subset of B-cell malignancies with a considerable hostile TME with M2-like TAMable to jeopardize anti-cancer immunityTherefore the possibility to boost innate anti-cancer immunity through this DEMs blockade could provide new therapeutic options to previous heavily pretreated relapsedrefractory MCL and CLL patients
Detailed Description:
MCL is an aggressive B-NHL with dismal prognosis with high probability of relapse after conventional immunochemotherapeutic regimen CLL is instead an incurable chronic B-cell malignancy with higher probability of relapse after several lines of conventional therapies and a non-negligible risk of progression into an aggressive lymphoma Further approaches are needed to provide valid alternatives for these relapsed and refractory diseases In these two settings TME is known to be involved in cancer cell survival and confers a negative impact on standard treatment efficacy and adoptive T cell immunity for which new immunotherapeutic agents could be an alternative approach in case of poor prognostic settings Within TME TAM are involved in improving tumor growth survival in MCL and CLL dampening immunotherapy as well Anti-CD47 mAb turned out to be a consistent DEMs that once blocked is able to improve phagocytosis and clearance of tumor cells in blood cancer CD24 has been recently validated as another DEMs in preclinical analysis in solid cancer Since CD24 is expressed during early phase of B-cell differentiation MCL and CLL might take advantage of the blockade of this signal since TAM and NCLs are strictly interconnected with their corresponding tumoral cells providing tumor cell proliferation and immune escape
To fulfill the purposes of this project collection of leftover patient-derived samples will be routinary performed at the time of diagnosis and at the time of relapse of the disease in this latter case with the aim to check any CD24 CD47 and CD20 surface expression modification on B-cell blasts eg clone selection with CD24CD47 upregulation after conventional regimen SIRP-α and Siglec-10 expression on patient-derived MonocyteMacrophage system expressing higher levels of DEMs ligands as potential mechanism of resistance after conventional therapy
Furthermore phagocytosis assays with samples obtained at the time of relapse will be compared with the equivalent experiments performed with the samples collected at the time of diagnosis to evaluate any potential differences
As previously described phagocytosis analysis will be based on a co-culture process that involves the use of the anti-CD24 antibody alone or in combination with other antibodies described in the secondary endpoint incubating with macrophages from healthy donor or from patient and patient tumor cells MCL or CLL this latter labeled with a fluorescent substance ie CFSE Macrophage staining with anti-CD11b-PE antibody and subsequent flow cytometric analysis will be performed the ratio between double stained macrophages CD11b-PECFSE and single stained macrophages CD11b-PE will provide the entity of phagocytosis which will be compared with the negative control and the other experimental conditions antibody combinations described later in the secondary endpoints The double staining of macrophages provides indirect results of phagocytosis if the macrophage phagocytes CFSE cells it will also acquire this staining in addition to that due to the anti-CD11b-PE antibody
Finally donor-derived macrophages will be isolated from PBMC obtained from leftover peripheral blood which remained within the circuit used for plateletpheresis of healthy donors As a matter of fact residual blood almost 15 ml can be found in the reservoir of this circuit that is normally trashed after the procedure Donors will sign informed consent for use of leftover material for research purposes and this project in particular
To fulfill the purposes of this project collection of leftover patient-derived samples will be routinary performed at the time of diagnosis and at the time of relapse of the disease in this latter case with the aim to check any CD24 CD47 and CD20 surface expression modification on B-cell blasts eg clone selection with CD24CD47 upregulation after conventional regimen SIRP-α and Siglec-10 expression on patient-derived MonocyteMacrophage system expressing higher levels of DEMs ligands as potential mechanism of resistance after conventional therapy
Furthermore phagocytosis assays with samples obtained at the time of relapse will be compared with the equivalent experiments performed with the samples collected at the time of diagnosis to evaluate any potential differences
As previously described phagocytosis analysis will be based on a co-culture process that involves the use of the anti-CD24 antibody alone or in combination with other antibodies described in the secondary endpoint incubating with macrophages from healthy donor or from patient and patient tumor cells MCL or CLL this latter labeled with a fluorescent substance ie CFSE Macrophage staining with anti-CD11b-PE antibody and subsequent flow cytometric analysis will be performed the ratio between double stained macrophages CD11b-PECFSE and single stained macrophages CD11b-PE will provide the entity of phagocytosis which will be compared with the negative control and the other experimental conditions antibody combinations described later in the secondary endpoints The double staining of macrophages provides indirect results of phagocytosis if the macrophage phagocytes CFSE cells it will also acquire this staining in addition to that due to the anti-CD11b-PE antibody
Finally donor-derived macrophages will be isolated from PBMC obtained from leftover peripheral blood which remained within the circuit used for plateletpheresis of healthy donors As a matter of fact residual blood almost 15 ml can be found in the reservoir of this circuit that is normally trashed after the procedure Donors will sign informed consent for use of leftover material for research purposes and this project in particular
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None