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Preventing follicular lymphoma progression and transformation through precision therapy

通过精准治疗预防滤泡性淋巴瘤进展和转化

基本信息

批准号：
10632106
负责人：
Wendy Beguelin
金额：
$ 42.02万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632106
关键词：
Affinity Apoptotic B-Cell Lymphomas B-Lymphocytes BCL2 gene Back Bypass CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Communication Centrocyte Clinical Trials Darkness Data Dendrites Dendritic Cell Therapy Dendritic Cells Disease Progression EZH2 gene Epigenetic Process FDA approved Failure Follicular Dendritic Cells Follicular Lymphoma Genes Genetic Goals Helper-Inducer T-Lymphocyte Histologic Human Immune Immune checkpoint inhibitor Immunity Immuno-Chemotherapy Immunologic Surveillance Immunologics Indolent Knowledge Light Lymphoma Lymphoma cell Lymphomagenesis Mutation Patients Precision therapeutics Proliferating Refractory Regimen Relapse Resistance Signal Transduction Somatic Mutation Structure of germinal center of lymph node T-Lymphocyte Testing Therapeutic Work design gain of function mutation immunological synapse immunological synapse formation in vivo inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma mimetics mutant neoplastic novel novel therapeutic intervention permissiveness preclinical development prevent programs receptor recruit therapeutic target therapy resistant tumor tumor eradication

项目摘要

ABSTRACT Follicular lymphomas (FL) are germinal center (GC) B-cell derived, slow-growing tumors. Although initially indolent, FLs are essentially incurable with many cases undergoing progression and a relapsing course during which they become increasingly resistant to therapy. Additionally, as many as 45% of cases undergo histologic transformation to an aggressive form of B-cell lymphoma, that is generally refractory to chemo-immunotherapy. Hence there remains a critical unmet need to understand how low-grade FLs survive and are maintained, and to develop rational therapeutic regimens able to prevent disease progression and transformation and eradicate these tumors. The genetic hallmark of FLs include BCL2 translocations and somatic mutations of epigenetic modifier genes such as EZH2. Histologically, FLs typically feature a rich microenvironment, most notably featuring extensive follicular dendritic cell (FDC) networks with dendrites making extensive contact with lymphoma cells. In recent work we showed that the main effect of EZH2 gain-of-function mutations in GC B-cells is to enable them to become less dependent of T-cell help and strengthen their immune synapse formation with FDCs, which induces aberrant proliferation and survival of GC centrocytes and hence formation of FLs and their unique lymphoma-permissive immune niche. It is notable that even though GC B-cells are highly T-cell dependent, FLs are generally resistant to T-cell augmentation therapies such as checkpoint inhibitors. EZH2 mutant GC B-cells do not require T-cell help and are unable to form stable interactions with T-cells that might otherwise suppress these tumors (which might explain checkpoint inhibitors failure). However, we find that EZH2 inhibitors can recruit CD4 and CD8 cells back into these lymphomas, which we propose may represent the major anti-tumor mechanism of this now FDA-approved treatment in FLs. Moreover we have shown that EZH2 inhibitors reduce apoptotic thresholds in primary human EZH2 mutant lymphoma cells and are highly synergistic with BH3 mimetics in vivo and are implementing a clinical trial combining Tazemetostat and Venetoclax for FL and DLBCL patients. Based on these considerations and other preliminary data we hypothesize that EZH2 mutant FLs are dependent on signals received from FDCs, most notably BAFF receptor. We propose that therapeutic targeting of the FDC-FL B-cell immune synapse will yield a lethal blow to FLs, especially when combined with EZH2 inhibitors to restore T-cell anti-lymphoma immunity and BH3 mimetics such as Venetoclax. We expect these treatments to prevent FL progression and transformation. Our goals for this proposal are to determine whether EZH2 mutant FL B-cells depend on FDCs for their survival, whether EZH2 inhibitors act through restoring interactions of FL B-cells with T-cells, and to leverage this information to test novel combination of therapeutic approaches to prevent progression of EZH2 mutant FLs and transformation to aggressive lymphoma.

摘要