61. Ascending Dose Trials of a Retroviral Replicating Vector (Toca 511) in Patients with Recurrent High-Grade Glioma: Clinical Update, Molecular Analyses, and Proposed Mechanism of Action

Abstract

We have conducted Phase 1 studies in patients with high grade glioma of a retroviral replicating vector (RRV), Toca 511 (vocimagene amiretrorepvec), based on an amphotropic murine gamma retrovirus encoding an optimized cytosine deaminase. The vector appears highly selective for tumor cells. Infected cells convert the antifungal drug 5-fluorocytosine (5-FC) delivered as an orally available extended-release formulation (Toca FC), into the antineoplastic drug 5-fluorouracil (5-FU). Toca 511 has been delivered by intratumoral injection (NCT01156584), injection into the tumor bed post-resection (NCT01470794), or by IV administration (NCT01985256). In all cases the treatment is well-tolerated. In animal models extensive infection of tumors (close to 100%) leads to control of tumor growth both in xenograft and syngeneic models. Limited access to tumor tissue post Toca 511 treatment in trial subjects, and lack of good markers of human glioblastoma cells in these heterogeneous primary tumors make it difficult to determine the extent of cancer cell infection but there is good evidence of selective tumor infection by PCR, RTPCR and IHC against the CD protein. Clinical data in both the first two trials (intratumoral and resection bed administration with 39 and 43 evaluable subjects respectively) show a favorable safety profile and extended overall survival (OS) compared to historical controls. In the resection study, for example, median OS was 13.6 months compared to 7-8 months in matched historical controls, and the OS at 24 months was 32%. In addition an RNA expression signature in untreated resected tumors that predicts long term survival in trial subjects has been identified from subjects that subsequently underwent tumor bed administration of Toca 511 and Toca FC. This signature does not normally correlate with survival in available public data sets. In immune competent orthotopic animal models, Toca 511 and 5-FC treatment leads to apparent tumor elimination and induction of strong antitumor immune responses by several mechanisms, including local elimination of myeloid derived suppressor cells. Subcutaneous re-implantation of the same tumors did not lead to tumor growth in animals treated up to a year before, whereas tumors did develop in control naive animals. Available data in the human trials are consistent with the immune response playing a significant role in the apparent clinical efficacy. Thus, clinically, treatment with Toca 511 and extended-release 5-FC (Toca FC) appears to selectively destroy tumor cells within the body, while leaving healthy cells unharmed. Toca 511 and Toca FC have been administered to more than 120 high grade glioma subjects in the three studies and, based on results from these trials, a phase 2/3 trial (Toca 5 has recently started recruitment (NCT02414165). The combination of clinical and preclinical data supporting this decision will be reviewed.