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

• 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
• 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' s lymphoma; mimetics; mutant; neoplastic; novel; novel therapeutic intervention; permissiveness; preclinical development; prevent; programs; receptor; recruit; therapeutic target; therapy resistant; tumor; tumor eradication

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 卵泡淋巴瘤（FL）是生发中心（GC）B细胞衍生的，生长缓慢的肿瘤。虽然最初 懒惰，FL本质上是无法治愈的，许多情况正在进行进展和复发过程 它们变得越来越抗治疗。此外，多达45％的病例发生组织学 转化为B细胞淋巴瘤的侵略性形式，通常对化学免疫疗法难治性。 因此 开发能够预防疾病进展和转化和消除的理性治疗方案 这些肿瘤。 FL的遗传标志包括Bcl2易位和表观遗传的体细胞突变 EZH2等修饰基因。在组织学上，FL通常具有丰富的微环境，最著名的是 具有大量的卵泡树突细胞（FDC）网络，带有树枝状网络，与之广泛接触 淋巴瘤细胞。在最近的工作中，我们表明了GC B细胞中EZH2功能获得突变的主要影响 是为了使他们能够减少对T细胞帮助的依赖，并加强其免疫突触形成 FDC诱导GC中心细胞的异常增殖和存活，因此形成了FL及其 独特的淋巴瘤 - 抗药性免疫利基。值得注意的是，即使GC B细胞是高度T细胞 依赖性FL通常对T细胞增强疗法（例如检查点抑制剂）具有抗性。 EZH2 突变的GC B细胞不需要T细胞帮助，并且无法与可能的T细胞形成稳定的相互作用 否则会抑制这些肿瘤（这可能解释了检查点抑制剂衰竭）。但是，我们发现EZH2 抑制剂可以将CD4和CD8细胞募集回这些淋巴瘤，我们建议这可能代表主要 现在在FLS中使用FDA批准的治疗的抗肿瘤机制。而且，我们已经证明了EZH2 抑制剂降低原代人EZH2突变淋巴瘤细胞中的凋亡阈值，并且高度协同作用 使用BH3 Mimetics在体内，并正在实施一项临床试验，该试验结合了tazemetostat和venetoclax for fl 和DLBCL患者。基于这些考虑因素和其他初步数据，我们假设EZH2 突变型FL取决于从FDC收到的信号，最著名的是BAFF受体。我们提出了这一点 FDC-FL B细胞免疫突触的治疗靶向将对FL产生致命的打击，尤其是在 结合EZH2抑制剂，以恢复T细胞抗淋巴瘤免疫力和BH3模拟物（如Venetoclax）。 我们期望这些处理能够防止FL的进展和转化。我们的这一建议的目标是 确定EZH2突变体B细胞是否依赖FDC的生存，EZH2抑制剂是否ACT。 通过恢复FL B细胞与T细胞的相互作用，并利用此信息来测试新型组合 防止EZH2突变体FL的进展并转化为侵略性的治疗方法 淋巴瘤。