Toca 511 Gene Therapy In Combination With 5-Fluorocytosine For Intratumoral Production Of 5-Fluorouracil In A Colon Cancer Metastasis Model

Abstract Despite advances in screening, colorectal cancer (CRC) remains the fourth most commonly diagnosed cancer and the second leading cause of cancer death for both men and women in the US. Approximately one half of patients with CRC develop liver metastases (mCRC). The standard treatment for mCRC is 5-fluorouracil (5-FU) based combination chemotherapy. 5-FU combination chemotherapy has extended the median survival of these patients from 6 to >20 months. We are pursuing a unique investigational approach to treat cancer via intratumoral production of 5-FU. Patients are first administered Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector (RRV) which selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) gene. In infected cells, the CD enzyme is expressed and converts 5-FC (flucytosine, an orally available anti-fungal drug) to the anti-cancer drug 5-FU in situ. The combination of Toca 511 with oral extended release 5-FC (Toca FC) is currently in clinical trials for recurrent High Grade Glioma (NCT01156584, NCT01470794, and NCT01985256). We tested the suitability of this approach for the treatment of mCRC in a mouse syngeneic liver metastasis model. CT-26-luciferase colon carcinoma cells were delivered via intrasplenic injection producing multiple tumor foci within the liver. Toca 511 was then delivered either by intrasplenic or intravenous injection followed by courses of 5-FC. Vector delivery to tumor was monitored by PCR. 5-FC and 5-FU were detected using LC/MS. The effect of treatment with Toca 511 and 5-FC in this mouse model of mCRC will be presented. Citation Format: Maria E. Rodriguez-Aguirre, Fernando Lopez Espinoza, Bryan Martin, Kader Yadiz, Tiffany T. Huang, Carlos E. Ibanez, Derek G. Ostertag, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins. Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2014-708