Targeting Latency Switch in EBV+ Lymphomas
Targeting Latency Switch in EBV+ Lymphomas
批准号:
10654011
负责人:
Lisa Giulino Roth
金额:
$64.84万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-01 至 2027-06-30
关键词:
AfricanAllogenicAntigen TargetingAntigensBurkitt LymphomaCell DeathCell TherapyCellsClinical TrialsCytotoxic T-LymphocytesDecitabineDevelopmentDiseaseEBV specific T-cellsEffector CellEpigenetic ProcessEpitopesEpstein-Barr Virus latencyEpstein-Barr Virus-Related LymphomaEpstein-Barr Virus-Related Malignant NeoplasmFutureGoalsHIVHigh Dose ChemotherapyHumanHuman Herpesvirus 4ImmuneImmune mediated destructionImmune responseImmunocompetentImmunologicsImmunotherapyIn VitroIndividualLymphomaMalignant NeoplasmsMediatingNatural Killer CellsNuclear AntigensOncogenicPatient-Focused OutcomesPhenotypeProteinsRecurrent diseaseResistanceResource-limited settingT cell responseT cell therapyT-LymphocyteTherapeuticUntranslated RNAViralViral AntigensViral GenomeViral ProteinsVirusVirus LatencyWorkanti-tumor immune responseimmune activationimmunogenicin vivolarge cell Diffuse non-Hodgkin&aposs lymphomalatent infectionnovel strategiesnovel therapeuticspharmacologicpreventprogramsresistance mechanismtargeted treatmenttherapeutic developmenttreatment strategytumortumor eradication
中文摘要
EBV相关淋巴瘤是侵袭性B-、T-和NK-细胞恶性肿瘤的异质组。在这些
在淋巴瘤中,EBV以潜伏状态存在,其中不产生感染性病毒,但产生有限数量的病毒性免疫缺陷病毒。
蛋白质表达。EBV+淋巴瘤逃避对EBV的免疫应答的一种机制是
通过潜伏期I程序,其中仅弱免疫原性Epstein巴尔核抗原1(EBNA 1)和
非编码RNA被表达。潜伏期I EBV+淋巴瘤包括伯基特淋巴瘤和许多EBV+淋巴瘤病例。
HIV相关的弥漫性大B细胞淋巴瘤这些亚型迫切需要新的治疗方法,
复发性疾病患者的结果令人沮丧(例如,Burkitt淋巴瘤的OS<20%)。在
此外,世界上许多病例发生在资源有限的环境中,
化疗不可行。我们对EBV+淋巴瘤未满足需求的方法是使用表观遗传学
重编程以将潜伏期I肿瘤转化为高免疫原性潜伏期II或III程序,从而使
对T细胞介导的杀伤敏感的肿瘤。使用高通量药理学筛选,我们确定了
低甲基化剂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,我们观察到地西他滨治疗潜伏期I肿瘤使耐药细胞对
通过同种异体EBV特异性T细胞的体外和体内杀伤。根据初步调查结果,我们
假设EBV+淋巴瘤中潜伏转换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应答。在
目前的建议,我们将开发一个合理的方法来使用表观遗传调制诱导潜伏期
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
需要根除潜伏期转换的EBV+淋巴瘤,包括其活化状态和功能,和
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,并开发治疗组合策略
最大化从潜伏期I转换为潜伏期II/III的细胞的百分比。最后,我们将建立
增强潜伏转换EBV+淋巴瘤的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I期EBV+淋巴瘤,利用表观遗传重编程诱导免疫原性病毒抗原,
其他免疫沉默肿瘤。这项工作的意义超出了淋巴瘤的所有EBV+
潜伏期有限的恶性肿瘤。
英文摘要
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.
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会议论文
Targeting Latency Switch in EBV+ Lymphomas
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批准号:10444456
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项目类别:
-
资助金额:$67.28万
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财政年份:2022
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负责人:Lisa Giulino Roth
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依托单位:
Rational Translation of EZH2 Targeted Therapy in Germinal Center B-cell Lymphoma
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批准号:9370942
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项目类别:
-
资助金额:$17.12万
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财政年份:2017
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负责人:Lisa Giulino Roth
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依托单位:
海外基金