Neoplasms

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Lymphoma

Leukemia

Leukemia, Lymphoid

Hematologic Neoplasms

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Mantle-Cell

Neoplasms by Histologic Type

Hematologic Diseases

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Lymphoma, Non-Hodgkin

Lymphosarcoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Mantle Cell Lymphoma

Andrea Aroldi

Mantle-cell Lymphoma (MCL) is a B-cell non-Hodgkin's lymphoma (NHL) with heterogeneous behavior,ranging from indolent phenotype to highly aggressive and drug resistant cases with dismal prognosis.Disease progression and drug resistance may be generated by Tumor Microenvironment (TME),owing 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 system.Similarly, 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 well.Higher number of circulating abnormal B cells is secondary to a balance between increased proliferation and decreased apoptosis activities,sustained by signals also deriving from TME.As a matter of fact,TME 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 survival.Recently, cancer-expressed CD47 was found to be involved in tumor immune escape through interaction with Signal Regulatory Protein-α (SIRP-α) expressed by TAM,being able to quench phagocytosis. Interestingly,"Don't Eat Me" signal (DEMs) blockade with anti-CD47 monoclonal Antibody (mAb) showed promising activity in pretreated NHL,through increase of phagocytosis by TAM.CD24 was also demonstrated to be involved in DEMs in solid cancer.As a matter of fact, tumor-expressed CD24 promotes immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin10 (Siglec-10),expressed by TAM with immunosuppressive phenotype (M2-like).In 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 vivo.It 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 CD24.In this setting,CD24 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 TAM,able to jeopardize anti-cancer immunity.Therefore, the possibility to boost innate anti-cancer immunity through this DEMs blockade could provide new therapeutic options to previous heavily pretreated relapsed/refractory MCL and CLL patients.

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 (e.g., clone selection with CD24/CD47 upregulation after conventional regimen), SIRP-α and Siglec-10 expression on patient-derived Monocyte/Macrophage 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 (i.e., CFSE). Macrophage staining (with anti-CD11b-PE antibody) and subsequent flow cytometric analysis will be performed: the ratio between double stained macrophages (CD11b-PE+/CFSE+) 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.

"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.

Rate of phagocytosis of human M2-like macrophages co-cultured with MCL and CLL blast cells treated with anti-CD24 mAb.

* Rate of phagocytosis with patient-derived monocytes system and autologous MCL/CLL blast cells with anti-CD24 mAb.
* Rate of phagocytosis with different mAb combinations and statistical comparison (anti-CD24, anti-CD47, anti-CD20, anti-CD24+anti-CD47, anti-CD47+anti-CD20, anti-CD24+anti-CD20, anti-CD47+anti-CD24+anti-CD20 mAbs) for donor-derived and patient-derived human macrophages co-cultured with human MCL and CLL blast cells derived from patients.

University of Milano Bicocca

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Tamoxifen

Hormones

Estrogens

Goserelin

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Anastrozole

Toremifene

Antineoplastic Agents, Hormonal

Patients who took tamoxifen or Fareston for 2-3 years were randomized into 2 groups (335 patients for each group). One group would switch to receive Zoladex 3.6mg depot subcutaneously every month and Aromidex 1mg/d po for another 3-2 years

Patients who took tamoxifen or Fareston for 2-3 years were randomized into 2 groups (335 patients for each group). One group would receive TAM 20mg/d treated for 3-2 years.

Zoladex+AI

Zhi-min Shao, MD

Ya-jie Ji, MD

The present study is a randomized open-label -phase III study that aims to compare the efficacy of Zoladex® combined with Aromidex® for 3-2 years after SERMs (tamoxifen and Fareston®) as an adjuvant therapy for 2-3 years with the efficacy of tamoxifen up to 5 years for premenopausal breast cancer women with hormone receptor positive, lymph node positive or tumor ≥4cm. According to St. Gallen's guideline, hormone receptor positive was defined as endocrine responsive and endocrine response uncertain categories (table 3-1), and only those with ER or PR expression undetectable were considered as HR negative. The pathological evaluation of axillary lymph node could be done by sentinel node biopsy (SNB) when axillary nodes were clinically impalpable accompanied with axillary lymph node dissection (ALND) or directly through ALND when axillary nodes appeared to be positive in clinical examination. Based on the operating standard of local medical institution, identifying the numbers of lymph nodes to do the pathological evaluation and to do the dissection of I- or II-station nodes accurately.

Adjuvant AI Combined With Zoladex

A Randomized ,Open Label Study Comparing the Efficacy of Zoladex® Combined With Arimidex® for 3-2 Years After Selective Estrogen Receptor Modulators (SERMs) as an Adjuvant Therapy for 2-3 Years Versus Continuing Tamoxifen up to 5 Years for Premenopausal Early Breast Cancer Patients With Hormone Receptor Positive, Lymph Node Positive or Tumor≥ 4cm.

Disease free survival (DFS): DFS related events ware defined as local recurrence, distant metastasis, secondary primary cancer or death, whichever occurred first.during follow up

Bilateral secondary primary breast cancer morbidity

Osteoporosis related events ( BMD and bone fracture incidence)

Other adverse events (Gynecological events, blood lipids, thrombosis, cardiovascular diseases, and etc.)

Fudan University

Fudan University Shanghai Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca
Adjuvant AI Combined With Zoladex	NCT01352091	Breast Cancer	Zoladex+AI TAM	18 Years -	Fudan University
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca
"Don't Eat me" Signal in Hematological Malignancies: CD24 as New Target to Improve Anti-cancer Immunity.	NCT05888701	Mantle-cell Lym... B Cell Chronic ...		18 Years -	University of Milano Bicocca

Spots Global Cancer Trial Database for tam

Every month we try and update this database with for tam cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for tam

Every month we try and update this database with for tam cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for tam cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.