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

描述(申请人提供)：在美国，每年约有18.5万人被诊断出患有原发或转移性脑瘤，这是导致20-39岁年轻人死亡的第三大原因。在脑肿瘤中，恶性胶质瘤是最常见和最具侵袭性的恶性肿瘤。胶质瘤似乎能够通过Fas/Fas配体(Fas-L)途径诱导T细胞凋亡。这一机制允许它们通过降低细胞介导的免疫力来规避免疫监视。脑肿瘤治疗使用免疫调节剂，如白介素类(IL)，增加了活跃的T淋巴细胞群体的招募，并已被证明是一种有效的策略，在该疾病的实验模型。然而，由于肿瘤分泌Fas-L，IL募集的瘤周T细胞通过跨膜Fas受体被激活，从而启动Caspase-3介导的凋亡级联反应。利用核糖核酸干扰技术，可以沉默肿瘤来源的Fas-L基因，减少T细胞凋亡，从而提高抗肿瘤反应，增强白细胞介素性治疗的效果。RNAi序列可以通过逆转录病毒传递，从而保证了组成性的转染。在这项建议中，将研究通过逆转录病毒传递的Fas-L RNAi序列对实验性胶质瘤的治疗效果。这种治疗方式的效果将被单独研究，并将与局部注射的IL并入注射微球中。Fas-L RNA干扰序列的治疗有望降低肿瘤来源的Fas-L的水平，从而降低T细胞凋亡率，增加瘤周T细胞的数量。这样的效应应该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时间。此外，局部递送的IL微球的疗效应得到提高。以这种方式传递Fas-L RNAi的潜在益处可能适用于几种免疫豁免策略中具有Fas/Fas-L途径的恶性肿瘤。

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.