Temozolomide (TMZ), an oral alkylating agent, is the standard chemotherapy treatment for patients with newly diagnosed glioblastoma multiforme (GBM), the most common and aggressive form of primary brain cancer in adults. Investigation of this new agent in patients with newly diagnosed HGG requires an understanding of the interaction of Toca 511 and Toca FC treatment with the current first-line standard of care for these tumors.
Toca 511, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently in clinical trials for recurrent high-grade glioma. 2 The RRV-CD vector has specificity for replicating cells, and replication in non-malignant cells in vivo appears highly restricted. We have previously shown that Toca 511 (vocimagene amiretrorepvec), a non-lytic, amphotropic retroviral replicating vector (RRV), 1 can successfully and safely deliver a functional, optimized cytosine deaminase ( CD) gene to tumors in orthotopic glioma models. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma. 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.
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