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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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阻滞在复发或难治性的经典霍奇金淋巴瘤（CHL）和弥漫性大B细胞淋巴瘤（DLBCL）患者的子集中有效，但大多数B细胞淋巴瘤患者对这种抗PD-1免疫疗法没有反应。因此，有必要制定新的治疗策略来增强对Mmunotherapy的反应。然而，它仍然鲜为人知，如何增强肿瘤免疫原性以改善抗肿瘤免疫反应。在这方面，组蛋白脱乙酰基酶（HDAC）抑制剂可能是实现此类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/或调节免疫细胞功能。然而，到目前为止，大多数测试的HDAC抑制剂（HDACI）在将癌症视为单一药物方面并不是很有效。这可能是由于以下事实：不同的HDACI会在癌症或正常细胞中引起高度可变的生物学作用。此外，尽管已经对HDACI对肿瘤细胞的细胞毒性作用进行了广泛的研究，但它仍然不足以了解HDACI如何影响免疫细胞以及HDACI在抗肿瘤免疫中的精确作用。重要的是，它在很大程度上尚不清楚如何对癌症进行分层以鉴定HDACI敏感的亚型。在此应用中，我们建议阐明新开发的HDACI使B细胞淋巴瘤对PD-1治疗的敏感，并鉴定出预测HDACI和抗PD1抗体联合治疗的功效的生物标志物。因此，我们提出的研究可能通过开发新的治疗策略来促进该领域的一步，以靶向抗药性降低，靶向抗PD-1阻断的癌症。最近，我们通过XRCC4的谱系特异性缺失，DNA修复基因和TRP53在活化的B细胞中建立了G1XP淋巴瘤的独特小鼠模型。我们的初步数据表明，G1XP淋巴瘤类似于人类B细胞淋巴瘤的特征，并提供了一个独特的实验平台，用于测试靶向具有降低免疫原性的新疗法。我们的目的是开发新型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，用于B细胞淋巴瘤的人源化小鼠模型以及我们新开发的HDACI检验假设。