Intravenous delivery of toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue
Walbert T, Bota D, Vogelbaum M, Kalkanis S, Liau L, Mikkelsen T, Gruber H, Shorr J, Rodriguez-Aquirre M, Ostertag D, Mitchell L, Jolly D, and Cloughesy T. Intravenous delivery of toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue. Neuro-Oncology 2017; 19(suppl 6):vi30-vi31.
Toca 511 (vocimagene amiretroprepvec) is an investigational, conditionally lytic, retroviral replicating vector that encodes an optimized yeast cytosine deaminase (CD) gene. The CD gene converts the prodrug, Toca FC (investigational, extended-release 5-fluorocytosine), into the chemotherapeutic, 5-FU in infected tumors. In a Phase 1 study (NCT01985256), Toca 511 was injected intravenously for 1, 3, or 5 days to patients with recurrent high grade glioma. Tumors were subsequently resected, and Toca 511 was injected into the resection cavity walls. At the time of resection, tissue from various regions of the tumor was collected and processed for quantitative PCR analysis of CD RNA and DNA. Tissue from corresponding locations was fixed for assessment of CD protein expression by immunohistochemistry (IHC). Expression of CD protein was quantified based on immunofluorescence signal and was shown to co-localize in cells with detectable levels of gag, a viral structural protein. CD protein expression by IHC was assessed in tissue from locations that corresponded with samples positive for CD by PCR and ranged from 1.16% to 10.4% area of the field. These data show that intravenous delivery of Toca 511 results in appreciable deposition of vector in the tumor. Further, we have observed an inverse correlation between T cell infiltrate in the tumor microenvironment and clinical benefit in a complementary Phase I study in which Toca 511 was solely delivered into the resection cavity. Therefore, the nature of the study design described herein, which uses IV delivery of Toca 511, provides a unique opportunity to assess the spatial relationship between CD protein expression and histological features of the tumor. Immunohistochemical assessment to determine spatial correlates between CD protein and T cells, T regulatory cells, and immunosuppressive myeloid cells will be presented. Updated clinical response data will also be presented.