Difficulties of drug delivery across the blood-brain barrier (BBB) and failure to eliminate cancer stem cells (CSCs) are believed to be the major causes of tumor recurrences in children with medulloblastoma (MB). Seneca Valley virus-001 (SVV-001) is a naturally occurring oncolytic picornavirus that can be systemically administered. Here, we report its antitumor activities against MB cells in a panel of 10 primary tumor-based orthotopic xenograft mouse models. We found that SVV-001 killed the primary cultured xenograft cells, infected and replicated in tumor cells expressing CSC surface marker CD133, and eliminated tumor cells capable of forming neurospheres in vitro in 5 of the 10 xenograft models. We confirmed that SVV-001 could pass through BBB in vivo. A single i.v. injection of SVV-001 in 2 anaplastic MB models led to widespread infection of the preformed intracerebellar (ICb) xenografts, resulting in significant increase in survival (2.2-5.9-fold) in both models and complete elimination of ICb xenografts in 8 of the 10 long-term survivors. Mechanistically, we showed that the intracellular replication of SVV-001 is mediated through a subverted autophagy that is different from the bona fide autophagic process induced by rapamycin. Our data suggest that SVV-001 is well suited for MB treatment. This work expands the current views in the oncolytic therapy field regarding the utility of oncolytic viruses in simultaneous targeting of stem and nonstem tumor cells.

Susceptibility of activated T cells to apoptosis must be tightly regulated to ensure sufficient T cell progeny for an effective response, while allowing a rapid depletion of them at the end of the immune response. We show here that a previously isolated, NF-B͞rel target gene IEX-1 (Immediate Early response gene X-1) is highly expressed in T cells at early stages of activation, but declines with a prolonged period of activation time, coincident with an increased susceptibility of T cells to apoptosis during the late phases of an immune response. Transgenic expression of IEX-1 specifically in lymphocytes impaired apoptosis in activated T cells, extended a duration of an effectorphase of a specific immune response, and increased the accumulation of effector͞memory-like T cells and the susceptibility to a lupus-like autoimmune disease. Our study demonstrated an antiapoptotic effect of IEX-1 on T cell apoptosis triggered by ligation of Fas and T cell receptor (TCR)͞CD3 complex. The ability of extending life expectancy of T effectors, in line with a decrease in its expression following prolonged T cell activation, suggests a key role for IEX-1 in regulating T cell homeostasis during immune responses.antiapoptosis ͉ autoimmunity ͉ NF-B ͉ T cells I mmune responses are initiated when resting T cells are triggered by antigen͞MHC complexes to undergo clonal expansion and differentiation into effector populations. This response is followed by a rapid depletion of T effectors through apoptotic pathways to reduce the risk of autoimmunity (1-3). Therefore, lifespans of T effectors are critical not only in determining the duration of an immune response, but also in preventing from autoimmunity. Compelling evidence suggests that NF-B͞rel transcription factors play a pivotal role in linking between an innate and an adaptive immune response (4). However, the underlying mechanisms are not completely understood, one of which may be to extend the lifespan of T effectors by activation of NF-B͞rel transcription factors as a result of copious proinflammatory cytokines released during innate immune responses (5). In support, considerable studies indicate that activation of NF-B͞rel transcription factors promotes the survival of a variety of cells both in vitro and in vivo (6-9).IEX-1 (Immediate Early response gene X-1), also named IER3, p22͞PRG1, Dif-2, or mouse homology gly96, was isolated by several groups, but its function remains controversial (10-13). IEX-1 is a NF-B͞rel target gene and its promoter region contains a regulation site for NF-B transcription factor (14, 15). It can be rapidly up-regulated by various activators of the NF-B͞rel transcription factors such as TNF-␣, IL-1␤, PMA (phorbol 12-myristate 13-acetate), growth factors, viral infection, lipopolysaccharide (LPS), irradiation, etc. (10-13, 16-18). IEX-1 was shown to inhibit cell proliferation in some cells, but it appeared to accelerate cell cycle progression in others (11,(19)(20)(21). It was also reported to promote apoptosis in 293 and HeLa cells under serum depriv...