Breakthrough Technology   Why Gene Transfer is Promising We believe gene transfer is a promising approach for treating cancer. Unlike current conventional cancer treatments such as cytotoxic chemotherapy and radiation therapy, gene transfer has the potential to enable delivery of high concentrations of cancer killing drugs selectively to cancer tissue while leaving healthy tissue unharmed. The genes serve as the instructions for producing therapeutic proteins that are designed to kill the cancer cells directly. We believe gene transfer has the potential to be highly effective, with fewer side effects compared to conventional cancer treatment. Tocagen believes its proprietary gene transfer technology represents an important scientific advance over challenges discovered with prior gene transfer approaches. Initially, other research groups used non-replicating viruses, which lacked the ability to deliver the therapeutic gene throughout the entire cancer resulting in disappointing clinical efficacy. More recently other researchers have evaluated replicating oncolytic viruses but these viruses may have limitations due to rapid clearance by the patient's immune response against the virus. We believe Tocagen's technology platform can overcome these challenges and now may be able to fulfill the promise of gene transfer as a treatment for cancer. Our Breakthrough CAGT Technology Toca 511, also known as vocimagene amiretrorepvec [pronounced "voe sim' a jeen am i ret roe rep vek"], is the key novel component of Tocagen’s first Product Candidate, Toca 511 & Toca FC. Toca 511 was developed using our breakthrough Controlled Active Gene Transfer (CAGT) technology. The CAGT platform is a Retroviral Replicating Vector (RRV) that carries the complete complement of viral genes (gag, pol, env) which allow viral replication and subsequent delivery of a therapeutic gene throughout a tumor. RRV’s replicate by budding from the host cell, leaving the host cell intact. This budding mechanism allows cancer cells to become “factories” for generating RRV particles, which can then spread through the tumor. With this unique budding mechanism, a single dose of RRV (e.g. Toca 511) may be sufficient to achieve persistent gene transfer throughout the tumor.     Click to Enlarge Image   Electron micrographs used with permission from: Retroviruses. JM Coffin, SH Hughes, and HE Varmus. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997. Page 30. Copyright © 1997, Cold Spring Harbor Laboratory Press.   The CAGT technology allows the RRV’s to hide and spread in cancer cells because cancer cells typically have genetic mutations resulting in defects in innate and acquired immunity. In contrast, RRV’s are controlled by the immune system in healthy cells resulting in selective infection of the cancer cells.   Click to Englarge Image   Data from in vivo pre-clinical animal studies demonstrate efficient gene delivery throughout a tumor within approximately 3 weeks, as shown below:   Click to Enlarge Image In contrast, non-replicating viruses cannot spread and oncolytic viruses often cause an inflammatory response that does not allow the oncolytic virus to “hide” from the immune system. The unique combination of features of CAGT vectors addresses this key challenge because they are designed to persistently infect cancer cells resulting in complete infection of a tumor. CAGT Technology Potential Advantages The CAGT platform is designed to enable efficient delivery of high concentrations of an anti-cancer drug selectively to the cancer cells while sparing healthy tissue. Preclinical animal models of brain cancer show that this targeted cancer killing approach is well tolerated and can result in tumor destruction and prolonged survival in nearly all rodent animals treated. Based on these data we believe Tocagen's CAGT technology platform may be used for the development of treatments for multiple tumor types and now may be able to fulfill the promise of gene transfer as a treatment for cancer. Programs Brain Cancer (High Grade Glioma) Product Candidates Toca 511 & Toca FC                                             Clinical Trials      Information About Tocagen's Clinical Trials     Related Brain Cancer Resources     Accelerate Brain Cancer Cure   American Brain Tumor Association   American Cancer Society   Dictionary of Cancer Terms   National Brain Tumor Society   National Cancer Institute   National Institutes of Health   Voices Against Brain Cancer       Privacy Policy | Terms of Use | www.tocagen.com   3030 Bunker Hill St. Suite 230  San Diego, CA 92109          Main (858) 412-8400  Fax (858) 412-8499  © Copyright 2012 Tocagen Inc.