PURPOSE: High-grade gliomas (HGGs) are central nervous system tumors with poor 
prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is 
a retroviral replicating vector encoding cytosine deaminase, which converts 
extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 
5-fluorouracil. According to preclinical studies, this therapy kills cancer 
cells and immunosuppressive myeloid cells in the tumor microenvironment, leading 
to T-cell-mediated antitumor immune activity. Therefore, we sought to elucidate 
this immune-related mechanism of action in humans, and to investigate potential 
molecular and immunologic indicators of clinical benefit from therapy.
PATIENTS AND METHODS: In a phase I clinical trial (NCT01470794), patients with 
recurrent HGG treated with Toca 511 and Toca FC showed improved survival 
relative to historical controls, and some had durable complete responses to 
therapy. As a part of this trial, we performed whole-exome DNA sequencing, 
RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood 
samples.
RESULTS: Genetic analyses suggest mutations, copy-number variations, and 
neoantigens are linked to survival. Quantities of tumor immune infiltrates 
estimated by transcript abundance may potentially predict clinical outcomes. 
Peak values of cytokines in peripheral blood samples collected during and after 
therapy could indicate response.
CONCLUSIONS: These results support an immune-related mechanism of action for 
Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are 
related to clinical benefit from treatment.