Targeting Latency Switch in EBV+ Lymphomas

EBV 淋巴瘤的靶向潜伏期开关

基本信息

批准号：
10444456
负责人：
Lisa Giulino Roth
金额：
$ 67.28万
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444456
关键词：
African Allogenic Antigen Targeting Antigens B-Lymphocytes Burkitt Lymphoma Cell Death Cell Therapy Cells Clinical Trials Cytotoxic T-Lymphocytes Decitabine Development Disease EBV specific T-cells Effector Cell Epigenetic Process Epitopes Epstein-Barr Virus latency Future Goals HIV High Dose Chemotherapy Human Human Herpesvirus 4 Immune Immune mediated destruction Immune response Immunocompetent Immunologics Immunotherapy In Vitro Individual Lead Lymphoma Malignant Neoplasms Mediating Natural Killer Cells Nuclear Antigens Oncogenic Patient-Focused Outcomes Pharmacology Phenotype Proteins Recurrent disease Resistance Resource-limited setting T cell response T cell therapy T-Lymphocyte Therapeutic Untranslated RNA Viral Viral Antigens Viral Genome Viral Proteins Virus Virus Latency Work anti-tumor immune response base immune activation immunogenic in vivo large cell Diffuse non-Hodgkin&apos s lymphoma latent infection novel strategies novel therapeutics prevent programs resistance mechanism targeted treatment therapeutic development treatment strategy tumor

项目摘要

EBV-associated lymphomas are a heterogenous group of aggressive B-, T-, and NK- cell malignancies. In these lymphomas, EBV exists in a latent state where infectious virus is not produced but a limited number of viral proteins are expressed. One mechanism by which EBV+ lymphomas escape the immune response to EBV is through the latency I program where only the weakly immunogenic Epstein Barr nuclear antigen 1 (EBNA1) and non-coding RNAs are expressed. Latency I EBV+ lymphomas include Burkitt lymphoma and many cases of HIV-associated diffuse large B-cell lymphoma. Novel therapies are urgently needed in these subtypes where the outcome for patients with relapsed disease is dismal (OS<20% in Burkitt lymphoma, for example). In addition, many of the world’s cases arise in resource limited settings where upfront treatment with high dose chemotherapy is not feasible. Our approach to this unmet need in EBV+ lymphomas is to use epigenetic reprogramming to convert latency I tumors to the highly immunogenic latency II or III program, thereby rendering tumors sensitive to T-cell mediated killing. Using a high-throughput pharmacologic screen, we identified the hypomethylating agent decitabine as a potent inducer of latency II and latency III antigens in latency I EBV+ lymphomas. Furthermore, we observed that decitabine treatment in latency I tumors sensitizes resistant cells to killing by allogeneic EBV-specific T-cells, both in-vitro and in-vivo. Based on our preliminary findings, we hypothesize that epigenetic induction of latency switch in EBV+ lymphoma induces an anti-tumor immune response capable of eradicating disease through cytotoxic T-cell recognition of latency II/III viral epitopes. In the current proposal we will develop a rational approach to the use of epigenetic modulation to induce latency switching and immune mediated cell death in EBV+ lymphomas. We will determine which immune effector cells are required to eradicate latency switched EBV+ lymphomas including their activation status and function, and will characterize the predominant viral antigens to which they are responding. We will also explore mechanisms of potential resistance to decitabine mediated latency-switching and develop therapeutic combination strategies that maximize the percentage of cells that convert from latency I to latency II/III. Finally, we will establish therapeutic approaches that enhance the immune destruction of latency switched EBV+ lymphomas. Collectively, this proposal will accomplish the rational development of an entirely novel approach to the treatment of latency I EBV+ lymphomas, utilizing epigenetic reprogramming to induce immunogenic viral antigens in otherwise immunologically silent tumors. This work has implications beyond lymphomas to all EBV+ malignancies with restricted latency.

EBV 相关淋巴瘤是一组异质的侵袭性 B 细胞、T 细胞和 NK 细胞恶性肿瘤。淋巴瘤中，EBV以潜伏状态存在，不产生传染性病毒，但病毒数量有限 EBV+ 淋巴瘤逃避 EBV 免疫反应的一种机制是表达蛋白质。通过潜伏期 I 程序，其中只有弱免疫原性 Epstein Barr 核抗原 1 (EBNA1) 和潜伏期 I EBV+ 淋巴瘤包括伯基特淋巴瘤和许多病例。这些亚型迫切需要 HIV 相关的弥漫性大 B 细胞淋巴瘤的新疗法。疾病复发患者的结果令人沮丧（例如，伯基特淋巴瘤的 OS<20%）。此外，世界上许多病例都发生在资源有限的环境中，这些环境中需要进行高剂量的前期治疗化疗是不可行的，我们针对 EBV+ 淋巴瘤这一未满足的需求的方法是使用表观遗传学。重编程将潜伏期 I 肿瘤转化为高免疫原性潜伏期 II 或 III 程序，从而使通过高通量药理学筛选，我们确定了对 T 细胞介导的杀伤敏感的肿瘤。低甲基化剂地西他滨作为潜伏期 II 和潜伏期 III 抗原在潜伏期 I EBV+ 中的有效诱导剂此外，我们观察到地西他滨治疗潜伏期 I 肿瘤可使耐药细胞变得敏感。根据我们的初步研究结果，我们在体外和体内均通过同种异体 EBV 特异性 T 细胞进行杀伤。随后，EBV+淋巴瘤中潜伏期开关的表观遗传诱导诱导了抗肿瘤免疫能够通过细胞毒性 T 细胞识别潜伏 II/III 病毒表位来根除疾病的反应。目前的建议是，我们将开发一种合理的方法来使用表观遗传调节来诱导潜伏期 EBV+淋巴瘤中的转换和免疫介导的细胞死亡我们将确定哪些免疫效应细胞。需要根除潜伏转换的 EBV+ 淋巴瘤，包括其激活状态和功能，以及将表征它们所响应的主要病毒抗原，我们还将探索机制。对地西他滨介导的潜伏期转换的潜在耐药性并制定治疗组合策略最大化从潜伏期 I 转换为潜伏期 II/III 的细胞百分比。增强潜伏转换 EBV+ 淋巴瘤免疫破坏的治疗方法。总的来说，该提案将完成一种全新治疗方法的合理开发潜伏期 EBV+ 淋巴瘤，利用表观遗传重编程诱导免疫原性病毒抗原这项工作对淋巴瘤以外的所有 EBV+ 肿瘤都有影响。潜伏期有限的恶性肿瘤。