*4.3. Oncolytic Retrovirus*

Replication-competent retroviruses are a relative newcomer to the OV field. These are single-stranded RNA viruses. Originally, retroviruses were applied in gene therapy approaches, however, it was later shown that replication competence of retroviruses can provide a powerful tool for gene delivery of anticancer agents in tumors [115]. Vocimagene amiretrorepvec (Toca 511) is a replicating γ-retrovirus derived from murine leukemia virus and is engineered to encode a yeast cytosine deaminase (CD) gene [116]. In the presence of the prodrug 5-fluorocytosin (5-FC), CD converts 5-FC to the potent anti-cancer drug 5-fluorouracil (5-FU). The results from a phase I clinical trial for recurrent high-grade gliomas showed that the median survival of the patients (*n* = 53) was 13.6 months with six patients showing complete response [21]. However, in a subsequent phase III study in 403 patients, clinical endpoints were not met [117].

New results from the earlier phase I clinical trial (NCT01470794) were recently published demonstrating that 86% of the patients that lived >2 years had neoantigens deriving from IDH1, PI3K3CA, EGFR, SYNE1 genes. Interestingly, only 26% of the patients with <2 years survival had neoantigens arising from these genes, suggesting that neoantigens arising from driver genes may support Toca+5-FC therapy response. Moreover, the numbers of M0 macrophages and NK cells at the tumor site at the time of treatment were associated with poor response [118]. It is conceivable that these cells contributed to clearance of the virus before its therapeutic effect could take place. Further investigation is needed to establish if the immune composition could serve as a predictive marker and whether this is also the case for other oncolytic viruses.
