GENO-30DISTINCT GENE EXPRESSION PROFILE THAT IS NOT A KNOWN SURVIVAL PREDICTOR IN TUMORS FROM LONG-TERM HIGH GRADE GLIOMA SURVIVORS TREATED WITH A RETROVIRAL REPLICATING VECTOR ENCODING YEAST CYTOSINE DEAMINASE

Abstract

A dose escalating clinical study (NCT01985256) using a retroviral replicating vector (RRV), Toca 511, in combination with oral Toca FC (extended-release 5-fluorocytosine [5-FC]) is ongoing to evaluate safety and preliminary efficacy of this investigational therapy in patients with recurrent HGG. Toca 511 (vocimagene amiretrorepvec) encodes a yeast-derived, codon-optimized and heat-stabilized cytosine deaminase (CD) that converts 5-FC to the anti-cancer drug 5-FU in infected tumors. This virus replicates preferentially in malignant tissue and may have wide application in cancer therapies. In the study discussed here, Toca 511 is injected into resection cavity walls at time of tumor resection, and followed with multiple courses of Toca FC. RNA sequencing results in subject tumor samples reveal a unique gene expression profile associated with survival in Toca 511-treated subjects, which may be predictive. RNA expression profiles of resected tumors from 27 subjects were obtained via next-generation sequencing. Quality RNA sequencing results were obtained from two or three spatially distinct pieces of tumor from each subject. Expression profiles from separate regions of the same tumor were generally more similar to each other than to expression profiles of other subjects' tumors, but considerable heterogeneity was observed. A disproportionate number of the subjects that survived greater than one year displayed a unique expression subtype profile in multiple tumor samples that was distinct from normal brain and resembled samples isolated and analyzed in an orthogonal study from non-enhancing regions at the advancing edge of GBM tumors. Expression profiles that tracked with survival in the current study were not in general prognostic in orthogonal primary tumor datasets from TCGA and Rembrandt. These results suggest underlying molecular features and pathological stage of the tumor may help define the ability of Toca 511 and Toca FC therapy to prolong survival. Multivariate analysis using molecular and clinical factors will be presented.