205. Cytotoxic and Immunotherapeutic Effects of Toca 511 and 5-Fluorocytosine in an Intraperitoneal Model of Metastatic Colorectal Cancer
Authors: Kader Yagiz, Daniel Mendoza, Maria Rodriguez-Aguirre, Fernando Lopez Espinoza, Carlos E. Ibañez, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins
Journal: Molecular Therapy (2016)

Toca 511 (vocimagene amiretrorepvec), a gamma retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD) gene, selectively replicates and spreads in tumors. In infected cells, CD enzyme is expressed and converts 5-FC (5-fluorocytosine, an orally-available anti-fungal drug) to 5-FU (5-fluorouracil), leading to both direct tumor cytotoxicity and extended immunotherapeutic effects in preclinical models. Toca 511 in combination with Toca FC (extended-release 5-FC) recently entered a Phase 2/3 trial (NCT02414165) in patients with recurrent HGG (high grade glioma). Toca 511 is also under investigation delivered via intravenous (IV) infusion followed by injection into the wall of the resection cavity (NCT01985256), followed by Toca FC, in patients with recurrent HGG. IV administration of vectors is minimally invasive, can easily be repeated if desired, and may be applicable to other tumor types including metastatic colorectal cancer (mCRC). Previously we have shown that IV delivery of Toca 511 in a mouse syngeneic mCRC liver model resulted in expression of CD in tumor foci, but not in adjacent normal liver, and followed by courses of 5-FC resulted in direct tumor response, improved survival, and a systemic anti-tumor immune response. Elevated circulating myeloid-derived suppressor cells (MDSC) are associated with advanced disease stages in CRC patients and failure of immunotherapeutic strategies. We further investigated the effect of intralesional administration of Toca 511 with 5-FC treatment on tumor recurrence and immune infiltrates in a model of CRC brain metastases. A significant decrease in MDSC in spleens and tumors was observed with Toca 511 and 5-FC compared to controls, via in situ production of 5-FU (p=0.03, p<0.0001; respectively). Currently, we are investigating the efficacy of Toca 511 and 5-FC in a mouse syngeneic intraperitoneal (IP) model. We identified the optimal delivery method for treatment of IP metastases, and evaluated survival after IV and IP vector delivery followed by courses of 5-FC. Treatment with Toca 511 and 5-FC led to an improved median survival compared to control. Systemic 5-FU has hematological toxicity even at low doses (20 mg/kg) in both naïve and CRC tumor-bearing mice which could have an adverse effect on anti-tumor immune responses. We further evaluated Toca 511 and 5-FC treatment compared to systemic 5-FU in terms of efficacy, hematologic toxicity, and induction of anti-tumor immune responses in the IP mCRC model. The effect of Toca 511 and 5-FC compared to systemic 5-FU on MDSC and other immune cell populations will be presented. Our data provides support for the development of Toca 511 and 5-FC as a unique approach targeting both the tumor and the immune system for the treatment of metastatic cancers such as mCRC. A phase 1 study of IV Toca 511 and Toca FC in solid tumors, including mCRC, is planned (NCT02576665).