Abstract 1413: Treatment of mouse liver and brain colon cancer metastases with Toca 511 and 5-fluorocytosine for intratumoral production of 5-fluorouracil leads to increased survival, induction of antitumor immune responses, and reduction of MDSC
Authors: Rodriguez-Aguirre Maria , Yagiz Kader , Lopez Espinoza Fernando , Mendoza Daniel , Huang Tiffany T. , Ibanez Carlos , Gruber Harry E. , Jolly Douglas J. , Robbins Joan 
Published: July 2016

Approximately 50% of patients with colorectal cancer (CRC) develop metastases (mCRC) during the course of disease, with liver the most frequent site. Standard treatment for mCRC is 5-fluorouracil (5-FU) based combination therapy, with median survival now &gt;20 months. As a result of prolonged survival with metastatic disease, incidence of brain metastases from colorectal cancer is increasing. Approved immunotherapeutic agents have had limited effect in mCRC except in the subset of subjects (3-6%) with deficient mismatch repair. Recent studies suggest myeloid-derived suppressor cells (MDSC) contribute to cancer immune evasion by suppressing T cell anti-tumor functions and modulating innate immune responses.

We are pursuing a unique approach to treat cancer via in situ production of 5-FU. Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector, selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) protein. In infected cells, CD enzyme is expressed and converts 5-FC (5-fluorocytosine, an oral anti-fungal drug) to 5-FU. Direct tumor cytotoxicity and extended immunotherapeutic effects have been reported using this approach.

Toca 511 and Toca FC (extended release 5-FC) is under investigation in subjects with primary brain tumors, delivered intratumorally (NCT01156584), by injection into the resection bed (NCT01470794, NCT02414165), or intravenously (NCT01985256). We tested the intravenous (IV) 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 in the liver. IV delivery of Toca 511 followed by courses of 5-FC resulted in tumor response, improved survival, and immune mediated inhibition of rechallenge with tumor. IV delivery resulted in expression of vector encoded transgene in tumor foci but not in adjacent normal liver. Similar published results have been obtained in a number of brain tumor models with Toca 511+5-FC including a CT26 colon carcinoma brain metastasis model. We further investigated the effect of Toca 511+5-FC treatment on CRC tumor-induced MDSC in the CT-26 brain metastasis model. Intracranial cell implantation and intratumoral Toca 511 vector injections were followed by one course of 5-FC. Expansion of MDSC occurred in brain tumors and spleens of tumor bearing animals. A significant decrease in MDSC in spleens and tumors was observed with Toca 511+5-FC treatment compared to control (p = 0.03, p&lt;0.0001; respectively).

The results reported here support the development of Toca 511 and Toca FC as a novel immunotherapeutic approach for patients with mCRC. A phase 1 study of IV Toca 511 and Toca FC in solid tumors, including mCRC, is planned (NCT02576665).

Citation Format: Maria Rodriguez-Aguirre, Kader Yagiz, Fernando Lopez Espinoza, Daniel Mendoza, Tiffany T. Huang, Carlos Ibanez, Harry E. Gruber, Douglas J. Jolly, Joan Robbins. Treatment of mouse liver and brain colon cancer metastases with Toca 511 and 5-fluorocytosine for intratumoral production of 5-fluorouracil leads to increased survival, induction of antitumor immune responses, and reduction of MDSC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1413.