UC Irvine

Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector. The vector infects human cells with selectivity for cancer cells because genome integration is dependent on cell division and viral replication is inhibited by innate and adaptive immune responses, defective in malignant tissues. Toca 511 spreads through cancer cells and stably delivers the gene for an optimized yeast cytosine deaminase that converts courses of the prodrug Toca FC (an investigational, extended-release version of 5-fluorocytosine) into 5-fluorouracil (5-FU). The combined treatment is designed to generate 5-FU in the tumor micro-environment, directly killing cancer cells, leading to activation of antigen presenting cells. 5-FU can also diffuse into nearby immunosuppressive myeloid cells and kill them, leading to further activation of the immune system against the tumor by removing important brakes on the lymphocytes. The safety, viral kinetics, immune response, and preliminary efficacy of Toca 511 and Toca FC have been investigated clinically since 2010 in three, open-label, ascending dose, Phase 1 studies of 126 treated patients with recurrent high grade glioma (rHGG), each evaluating different methods of Toca 511 administration (intratumoral injection, injection into the cavity wall following resection, and intravenous injection followed by resection and injection into the cavity wall). Repeated courses of oral Toca FC follow Toca 511 administration. Results to date include good tolerability; no persistent viremia; successful gene transduction within resected tumors: no evidence for clonality by vector insertion site analysis; and increased median overall survival compared to historical controls with all three methods of vector administration. Partial responses and complete responses with a median duration of initial response of > 26 months start approximately 6–19 months after Toca 511 administration, and are associated with a long term survival. Based on 18Nov2016 data, patients in the resection trial with Toca 5 enrollment criteria and dosing had a clinical benefit rate of 42 % (3CRs, 2PRs, 5 SDs of 24 patients). Examination of IDH1 mutation status shows patients with a response are either wildtype or mutant. Preliminary data from these studies supported initiation of a randomized, Phase 2/3 study in patients with rHGG (NCT02414165) in 2015. Updated pooled safety data, immune response findings, and efficacy data for the Phase 1 studies will be presented.