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.

抽象的滤泡性淋巴瘤 (FL) 是生发中心 (GC) B 细胞来源的、生长缓慢的肿瘤。虽然最初惰性的 FL 本质上是无法治愈的，许多病例在治疗期间会出现进展和复发。他们对治疗的抵抗力越来越强。此外，多达 45% 的病例接受组织学检查转化为侵袭性 B 细胞淋巴瘤，通常对化学免疫疗法无效。因此，仍然存在一个未满足的关键需求，即了解低等级 FL 如何生存和维护，以及制定能够预防疾病进展、转化和根除的合理治疗方案这些肿瘤。 FL 的遗传标志包括 BCL2 易位和表观遗传体细胞突变修饰基因，例如 EZH2。从组织学角度来看，FL 通常具有丰富的微环境，最显着的是具有广泛的滤泡树突状细胞 (FDC) 网络，树突与细胞广泛接触淋巴瘤细胞。在最近的工作中，我们表明 EZH2 功能获得性突变对 GC B 细胞的主要影响是让他们减少对 T 细胞帮助的依赖，并加强他们的免疫突触形成 FDC，诱导 GC 中心细胞的异常增殖和存活，从而形成 FL 及其独特的淋巴瘤允许免疫生态位。值得注意的是，尽管 GC B 细胞是高度 T 细胞由于依赖性，FL 通常对检查点抑制剂等 T 细胞增强疗法具有抵抗力。 EZH2 突变的 GC B 细胞不需要 T 细胞的帮助，并且无法与 T 细胞形成稳定的相互作用，而 T 细胞可能会否则会抑制这些肿瘤（这可能解释检查点抑制剂的失败）。然而，我们发现EZH2 抑制剂可以将 CD4 和 CD8 细胞招募回这些淋巴瘤中，我们认为这可能代表了主要的这种现已获得 FDA 批准的 FL 治疗方法的抗肿瘤机制。此外，我们还证明了 EZH2 抑制剂可降低原代人 EZH2 突变淋巴瘤细胞的凋亡阈值，并且具有高度协同作用体内含有 BH3 模拟物，并正在实施一项结合 Tazemetostat 和 Venetoclax 治疗 FL 的临床试验和 DLBCL 患者。基于这些考虑和其他初步数据，我们假设 EZH2 突变型 FL 依赖于从 FDC 接收的信号，尤其是 BAFF 受体。我们建议 FDC-FL B 细胞免疫突触的治疗靶向将对 FL 产生致命打击，尤其是当与 EZH2 抑制剂和 BH3 模拟物（如 Venetoclax）联合使用可恢复 T 细胞抗淋巴瘤免疫力。我们期望这些治疗能够预防 FL 进展和转化。我们此提案的目标是确定 EZH2 突变 FL B 细胞的生存是否依赖 FDC，EZH2 抑制剂是否起作用通过恢复 FL B 细胞与 T 细胞的相互作用，并利用这些信息来测试新的组合预防 EZH2 突变 FL 进展和向侵袭性转化的治疗方法淋巴瘤。