PROJECT 1: PROJECT SUMMARY Oncolytic virotherapy (OV) is a novel modality of anti-cancer therapy, which consists of using genetically engineered conditionally replicating viruses to target and destroy cancer cells. Such selectivity of viral replication is achieved by employing various strategies including transcriptional targeting where tumor selective promoter sequence is used to drive the virus replication and capsid modifications that can promote tumor specific binding of the therapeutic virus. Our group has developed duel targeted oncolytic adenovirus vector CARd-Survivin-pK7 (CARd-S-pk7) and extensively evaluated this vector for the treatment of malignant glioma in the preclinical setting. In this setting, CRAd-S-pk7 exhibits extensive anti-tumor activity in mice bearing intracranial human glioma xenografts, including the highly aggressive CD133+ glioma stem cell derived xenograft model and cooperates with conventional anti-glioma chemo- and radiotherapy. One of the major limitations of OV is poor intratumoral distribution. To overcome this problem our group has demonstrated that neural stem cells (NSCs) can be used as a cell carrier to enhance viral delivery. This form of carrier based OV can enhance viral distribution as well as replication within the tumor, which results in a much more potent anti-tumor response than local delivery of the therapeutic virus alone. Based on this work, we are now position to translate this into the clinical setting. We have completed all the FDA directed preclinical study, held a pre- Investigational New Drug (IND) meeting with the Food and Drug Administration (FDA) and completed all the necessary steps in securing an IND for a phase I clinical trial. The goal of this SPORE project is to evaluate the safety of NSCs-CRAd-S-pk7 in the phase I clinical trial as a therapeutic platform for patients with malignant glioma. Our specific aims are Specific Aim 1: To evaluate clinical responses in patients administered CRAd-S-pK7-loaded NSCs. Specific Aim 2: To investigate immune response in patients administered NSCs carrying CRAd-S-pK7. Specific Aim 3: Imaging-based evidence of NSC distribution and tumor response after NSCs-CRAd-S-pK7 treatment. !

PROJECT 1:!PROJECT NARRATIVE One of the major limitations of oncolytic virotherapy is poor intratumoral distribution. To overcome this problem our group has demonstrated that neural stem cells (NSCs) can be used as a cell carrier to enhance the delivery of a novel oncolytic adenovirus and increase the therapeutic efficacy of such combined strategy vs. local delivery of the virus alone.