ATIM-24. SYSTEMATIC IDENTIFICATION OF TOCA 511 RETROVIRUS INTEGRATION SITES AND MUTATION PROFILES IN TUMOR AND BLOOD SAMPLES FROM PATIENTS UNDERGOING INVESTIGATIONAL TREATMENT FOR RECURRENT HIGH GRADE GLIOMA CORRELATES WITH FAVORABLE CLINICAL SAFETY PROFILE

Abstract

Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector (RRV) based on a gamma retrovirus encoding a cytosine deaminase transgene that allows infected cells to selectively convert the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil. Toca 511 can be delivered by multiple routes, and is designed to selectively infect and spread in tumor cells, and through multiple mechanisms elicit an anti-tumor immune response. Toca 511 and Toca FC have been administered to >125 recurrent high grade glioma patients in three phase I studies (NCT01156584, NCT01470794, NCT01985256) and, based on evidence for safety and drug activity from these trials, a phase 2/3 trial (Toca 5) is in progress (NCT02414165). In addition, we investigated potential off-target (blood) viral infection, and whether such off-target events have potential toxicity. We also investigated the stability profile of Toca 511 genomes after infection of tumor and off-target tissue. To date, approximately 25% of patients show quantifiable viral DNA (LOQ 250 copies/mL) in blood. In all cases, quantifiable virus RNA and DNA signal was cleared from blood. We systematically mapped Toca 511 integration sites from patient samples with detectable virus and sequenced, at high depth, integrated Toca 511 genomes, and in some cases RNA genomes, from these samples. As reported for gamma retroviruses, Toca 511 integration profiles display a preference for integration near active transcription start sites. There was no evidence for clonal expansion of Toca 511 integrated sites or cells. Also there was no preferential insertion of sites nearby oncogenes. Toca 511 sequences display an array of mutations in the tumor and blood, often transitions consistent with cytidine deaminase (APOBEC) activity. The data provide molecular correlates to the previously reported clinical safety profile of Toca 511 and Toca FC treatment and provide support for the activity of Toca 511 and Toca FC treatment in humans.