Abstract
Oncolytic virotherapy represents a potentially innovative approach for patients with malignant glioma. A major obstacle to effective therapy has been effective delivery of an oncolytic virus to the tumor. For this first-in-human phase I clinical study, we developed a novel oncolytic adenovirus, CRADd-Survivin-pk7, which utilizes the survivin promoter and binds to heparan sulfate proteoglycans expressed on the surface of tumor cells. Survivin is overexpressed in gliomas and is also a radiosensitive promoter driving viral replication in glioma but not normal brain cells. The virus was then loaded onto a neural stem cell line, HB1.F.CD, and a clinical grade agent was produced and approved by the FDA (IND 17365). The FDA approved the use of the clinical product in the initial setting, not recurrence, for patients with grade III and IV gliomas. This clinical trial consists of two cohorts, resectable and unresectable tumors, each with a classical 3 + 3 design. After biopsy or resection, increasing doses of virus loaded stem cells are injected. Cohort 1 consists of 50 million stem cells (6.25x1010 vp/patient), cohort 2 consists of 100 million stem cells (1.25x1011 vp/patient) and cohort 3 consists of 150 million stem cells (1.875x1011 vp/patient). Within 14 days, each patient then starts standard chemoradiotherapy (TMZ/RT). Safety and toxicity occurring until the end of TMZ/RT (day 56) is the primary endpoint, changes in cytokines and T-cells subgroups are correlative secondary endpoints. The first patient was treated in May 2017, and we will report on the first cohorts of patients at the meeting. Combining stem cells with oncolytic viruses may open up new avenues for effective delivery of gene therapy and oncolytic virotherapy to malignant brain tumors.