Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model

摘要: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase (CD) gene to tumors in orthotopic glioma models. This agent, conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation patients recurrent high-grade . Temozolomide (TMZ) radiation the most frequently used first-line treatment for glioblastoma, common aggressive form of primary brain cancer adults. However, subsets certain genetic alterations do not respond well TMZ overall median survival who remains modest, suggesting that combinatorial approaches may be necessary significantly improve outcomes. We show vitro delays but does prevent RRV spread, nor interfere 511+5-FC-mediated cell killing tumor cells, vivo there no significant hematologic effect from combination 5-FC clinically relevant dose TMZ. A synergistic long-term advantage observed mice bearing TMZ-sensitive after administration followed by coadministration 5-FC. These results provide support this novel strategy newly diagnosed malignant glioma.