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.
|Jansen, Timothy; Tyler, Betty; Mankowski, Joseph L et al. (2010) FasL gene knock-down therapy enhances the antiglioma immune response. Neuro Oncol 12:482-9|