Developing newly combined therapeutic strategies for mature B cell lymphoma

开发成熟 B 细胞淋巴瘤的新联合治疗策略

• 批准号: 10366505
• 负责人: Jing Hong Wang
• 金额: $ 47.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10366505
• 关键词: ATAC-seq; Address; Affect; Antigens; B-Cell Activation; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; BCL2 gene; Back; Biological; Biological Markers; CD4 Positive T Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cancer cell line; Cells; Chromatin; Combination immunotherapy; Combined Modality Therapy; Critical Pathways; Cytostatics; DNA Repair Gene; Data; Development; Disease; Down-Regulation; Epigenetic Process; Exhibits; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Hodgkin Disease; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Knowledge; Ligands; Lymphocyte; Lymphoma; Major Histocompatibility Complex; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Modeling; Mus; Non-Hodgkin' s Lymphoma; Normal Cell; PD-1 blockade; Patients; Pattern; Phenotype; Prognosis; Protein Isoforms; Proteins; Public Health; Refractory; Relapse; Resistance; Role; Sampling; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Translating; Transplantation; Treatment Efficacy; Tumor Immunity; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Work; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer immunotherapy; cancer type; cellular targeting; clinical application; combinatorial; cytotoxic; design; efficacy testing; genome editing; humanized mouse; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; insight; interest; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; refractory cancer; response; small molecule; tumor; tumor growth

While PD-1 blockade is effective in relapsed or refractory classical Hodgkin lymphoma (cHL) and in a subset of diffuse large B cell lymphomas (DLBCL) patients, a majority of B cell lymphoma patients do not respond to such anti-PD-1 immunotherapy. Hence, it is necessary to develop new therapeutic strategies to enhance responses to mmunotherapy. However, it remains poorly understood how to enhance tumor immunogenicity to improve anti-tumor immune responses. In this regard, histone deacetylase (HDAC) inhibitors may serve as an attractive means to achieve such goals, e.g., by upregulating major histocompatibility complex (MHC) in cancer cell lines and/or modulating immune cells' functions. Nevertheless, most HDAC inhibitors (HDACi) tested so far are not very effective in treating cancers as a single agent; this may be due to the fact that different HDACi can cause highly variable biological effects in cancer or normal cells. Furthermore, although the cytotoxic effects of HDACi on tumor cells have been studied extensively, it remains poorly understood how HDACi affect immune cells and what precise role HDACi have in anti-tumor immunity. Importantly, it remains largely unknown how to stratify cancers to identify the HDACi sensitive subtypes. In this application, we propose to elucidate the mechanisms by which a newly developed HDACi sensitizes B cell lymphomas to PD-1 therapy, and identify biomarkers that predict the efficacy of combined treatment of HDACi and anti-PD1 antibody. Hence, our proposed studies may advance the field one step forward by developing novel therapeutic strategies to target cancers resistant to PD-1 blockade due to reduced immunogenicity. We recently established a unique mouse model of G1XP lymphomas by lineage-specific deletion of Xrcc4, a DNA repair gene, and Trp53 in activated B cells. Our preliminary data show that G1XP lymphomas resemble the features of human B cell lymphomas and provide a unique experimental platform for testing new therapies that target lymphomas with reduced immunogenicity. Our objective here is to develop novel combinatorial strategies to treat aggressive B cell lymphomas. To do so, we will test our hypothesis using mouse B cell lymphoma models, humanized mouse models for B cell lymphoma, and our newly developed HDACi.

虽然 PD-1 阻断对复发或难治性经典霍奇金淋巴瘤 (cHL) 和部分弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者有效，但大多数 B 细胞淋巴瘤患者对此类抗 PD-1 免疫疗法没有反应。因此，有必要开发新的治疗策略来增强对免疫疗法的反应。然而，如何增强肿瘤免疫原性以改善抗肿瘤免疫反应仍知之甚少。在这方面，组蛋白脱乙酰酶（HDAC）抑制剂可能作为实现这些目标的一种有吸引力的手段，例如通过上调癌细胞系中的主要组织相容性复合物（MHC）和/或调节免疫细胞的功能。然而，迄今为止测试的大多数 HDAC 抑制剂 (HDACi) 作为单一药物治疗癌症并不是非常有效。这 可能是由于不同的 HDACi 可以在癌症或正常细胞中引起高度可变的生物学效应。此外，尽管 HDACi 对肿瘤细胞的细胞毒作用已被广泛研究，但人们对 HDACi 如何影响免疫细胞以及 HDACi 在抗肿瘤免疫中的确切作用仍知之甚少。重要的是，如何对癌症进行分层以识别 HDACi 敏感亚型仍然很大程度上未知。在本申请中，我们建议阐明新开发的 HDACi 使 B 细胞淋巴瘤对 PD-1 疗法敏感的机制，并确定预测 HDACi 和抗 PD1 抗体联合治疗疗效的生物标志物。因此，我们提出的研究可能会通过开发新的治疗策略来针对因免疫原性降低而对 PD-1 阻断产生耐药性的癌症，从而推动该领域向前迈进一步。 我们最近通过在活化的 B 细胞中特异性删除 Xrcc4（一种 DNA 修复基因）和 Trp53，建立了一种独特的 G1XP 淋巴瘤小鼠模型。我们的初步数据表明，G1XP 淋巴瘤与人类 B 细胞淋巴瘤的特征相似，并为测试针对免疫原性降低的淋巴瘤的新疗法提供了独特的实验平台。我们的目标是开发新的组合策略来治疗侵袭性 B 细胞淋巴瘤。为此，我们将使用小鼠 B 细胞淋巴瘤模型、B 细胞淋巴瘤人源化小鼠模型以及我们新开发的 HDACi 来检验我们的假设。