"Enhancement of Brain Tumor Immunotherapy by Fas-L RNAi"

“Fas-L RNAi 增强脑肿瘤免疫治疗”

• 批准号: 7035873
• 负责人: Alessandro Olivi
• 金额: $ 15.96万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035873
• 关键词: CD95 molecule; RNA interference; T lymphocyte; apoptosis; brain neoplasms; cellular immunity; enzyme linked immunosorbent assay; glioma; immunomodulators; interleukin 12; interleukin 2; laboratory rat; microcapsule; neoplasm /cancer immunotherapy; northern blottings; therapy design /development; western blottings

DESCRIPTION (provided by applicant): Each year, approximately 185,000 people in the United States are diagnosed with a primary or metastatic brain tumor constituting the third leading cause of death in young adults ages 20-39. Among brain tumors, malignant gliomas are the most common and aggressive malignancies. Gliomas seem to be capable of inducing T-cell apoptosis through the Fas/Fas-ligand (Fas-L) pathway. This mechanism allows them to circumvent immune surveillance by decreasing cell mediated immunity. Brain tumor therapy using immune modulators such as interleukins (IL) increases the recruitment of active T lymphocyte populations and has proven to be an effective strategy in experimental models of the disease. However, due to tumor-secreted Fas-L, the peritumoral T-cells recruited by IL are activated through the trans-membrane Fas receptor, which initiates the caspase-3 mediated apoptotic cascade. Using RNA interference (RNAi) techniques, mRNA from tumor-derived Fas-L could be silenced and T cell apoptosis could be decreased, thus improving antitumor responses and potentiating the effect of interleukin therapy. RNAi sequences can be delivered by retroviruses, guaranteeing a constitutive transfection. In this proposal, the effect that treatment with Fas-L RNAi sequences delivered via retroviruses has on experimental gliomas will be investigated. The effect of this treatment modality will be studied alone and in combination with locally delivered IL incorporated into injectable microspheres. Treatment with Fas-L RNAi sequences is expected to decrease levels of tumor-derived Fas-L, therefore decreasing the rates of T cell apoptosis and increasing the populations of peritumoral T cells. Such an effect should allow a more consistent cell-mediated anti-tumor response able to prolong survival in animal models. Furthermore, the efficacy of locally delivered IL microspheres should be enhanced. The potential benefit of Fas-L RNAi delivered in this fashion could be applicable to several malignancies that have the Fas/Fas-L pathway among their immune privilege strategies.

描述（由申请人提供）：每年，美国约有185,000人被诊断出患有原发性或转移性脑肿瘤，构成20-39岁年轻人的第三大死亡原因。在脑肿瘤中，恶性神经胶质瘤是最常见和侵略性的恶性肿瘤。神经胶质瘤似乎能够通过FAS/FAS-配体（FAS-L）途径诱导T细胞凋亡。这种机制使他们能够通过降低细胞介导的免疫力来规避免疫监测。使用白细胞介素（IL）等免疫调节剂的脑肿瘤治疗增加了活跃的T淋巴细胞群体的募集，并已证明是该疾病实验模型的有效策略。但是，由于肿瘤分泌的FAS-L，IL募集的周围T细胞通过反膜FAS受体激活，该跨膜FAS受体启动caspase-3介导的凋亡级联反应。使用RNA干扰（RNAI）技术，可以沉默的肿瘤衍生的FAS-L的mRNA可以降低T细胞凋亡，从而改善抗肿瘤反应并增强白介素治疗的作用。 RNAi序列可以通过逆转录病毒递送，以保证本构转染。在此提案中，将研究通过逆转录病毒传递的FAS-L RNAI序列的治疗对实验性神经胶质瘤的影响。该治疗方式的效果将单独研究，并结合局部递送的IL融合到注射的微球中。预计用FAS-L RNAI序列的治疗将降低肿瘤衍生的FAS-L水平，从而降低T细胞凋亡的速率并增加周围T细胞的种群。这种影响应允许更一致的细胞介导的抗肿瘤反应能够延长动物模型的生存。此外，应增强本地传递的IL微球的功效。以这种方式传递的FAS-L RNAi的潜在好处可能适用于几种在其免疫特权策略中具有FAS/FAS-L途径的恶性肿瘤。