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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：
10590693
负责人：
Jing Hong Wang
金额：
$ 45.19万
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/10590693
关键词：
ATAC-seq Address Affect Antigen Presentation B-Cell Activation B-Cell Lymphomas B-Cell NonHodgkins Lymphoma Back Biological 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 Prediction of Response to Therapy 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 biomarker identification cancer cell cancer immunotherapy cancer type cellular targeting clinical application combinatorial cytotoxic design efficacy evaluation efficacy testing genome editing humanized mouse immunogenic immunogenicity immunoregulation improved in vivo inhibitor 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 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阻断对复发或难治性经典霍奇金淋巴瘤（cHL）和一部分弥漫性大B细胞淋巴瘤（DLBCL）患者有效，但大多数B细胞淋巴瘤患者对这种抗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治疗的反应。然而，如何增强肿瘤免疫原性以改善抗肿瘤免疫反应仍然知之甚少。在这方面，组蛋白去乙酰化酶（HDAC）抑制剂可能是实现这一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体（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很有效；这