Targeting Latency Switch in EBV+ Lymphomas

EBV 淋巴瘤的靶向潜伏期开关

• 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
• 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' s lymphoma; latent infection; novel strategies; novel therapeutics; prevent; programs; resistance mechanism; targeted treatment; therapeutic development; treatment strategy; tumor

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性的侵袭性B细胞、T细胞和NK细胞恶性肿瘤。在这些 淋巴瘤，EBV以潜伏状态存在，不产生传染性病毒，而是有限数量的病毒 蛋白质被表达出来。EBV+淋巴瘤逃避EBV免疫反应的一个机制是 通过潜伏期I编程，只有弱免疫原性的Epstein Barr核抗原1(EBNA1)和 表达非编码RNA。潜伏期I EBV+淋巴瘤包括Burkitt淋巴瘤和许多病例 HIV相关弥漫性大B细胞淋巴瘤。这些亚型迫切需要新的治疗方法 复发患者的结果令人沮丧(例如，Burkitt淋巴瘤的OS&lt；20%)。在……里面 此外，世界上许多病例发生在资源有限的情况下，在这种情况下，预先进行大剂量治疗 化疗是不可行的。我们对EBV+淋巴瘤这种未得到满足的需求的处理方法是使用表观遗传学 重新编程以将潜伏期I肿瘤转换为高度免疫原性潜伏期II或III程序，从而呈现 肿瘤对T细胞介导的杀伤敏感。使用高通量的药理学筛选，我们确定了 去甲基化药物地西他滨作为潜伏期I EBV+中潜伏期II和潜伏期III抗原的有效诱导剂 淋巴瘤。此外，我们观察到在潜伏期i肿瘤中地西他滨治疗使耐药细胞对 体外和体内同种异体EBV特异性T细胞的杀伤作用。根据我们的初步调查结果，我们 假设EBV+淋巴瘤潜伏期转换的表观遗传诱导诱导抗肿瘤免疫 能够通过细胞毒性T细胞识别潜伏期II/III病毒表位而根除疾病的反应。在 目前的建议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+淋巴瘤的转归和免疫介导的细胞死亡。我们将确定哪种免疫效应细胞 是根除潜伏期转换EBV+淋巴瘤所必需的，包括它们的激活状态和功能，以及 将表征它们对其产生反应的主要病毒抗原。我们还将探索机制 研究地西他滨介导的潜伏期转换的潜在耐药性，并开发联合治疗策略 将潜伏期I转换为潜伏期II/III的细胞百分比最大化。最后，我们将建立 加强潜伏期转换型EBV+淋巴瘤免疫破坏的治疗方法。 总的来说，这一建议将实现一种全新的治疗方法的合理发展。 潜伏期I EBV+淋巴瘤，利用表观遗传重编程诱导免疫原性病毒抗原 否则就是免疫沉默的肿瘤。这项研究不仅对淋巴瘤，而且对所有EBV+都有影响 潜伏期受限的恶性肿瘤。