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Spotlight on TOCA 511

TOCA 511: New Treatment for Recurrent High Grade Gliomas?

The work of Noriyuki Kasahara, MD, PhD.

Dr. Kasahara joined the Departments of Cell Biology and Pathology at the University of Miami (UM) Miller School of Medicine in 2014. He has been working in the field of cancer research and gene therapy for 25 years and spent the last 10 years as the Director of the Vector Shared Resource & Core Facility at University of California, Los Angeles (UCLA). Dr. Kasahara’s main focus is cancer gene therapy, a promising approach in which genes are delivered directly to cancer cells. These genes can serve as the blueprint for making new therapeutic proteins that could attack the cells directly or provoke an immune response so that the body rejects the cells. While this method is more effective and has fewer side effects than current chemotherapy, it has been difficult to find ways of delivering genes to tumors. Many strategies for gene therapy have involved the use of certain viruses as vehicles (“vectors”) for gene delivery, because viruses have evolved efficient ways to insert their genes into human cells. In early vectors, the viral genes that naturally allowed the virus to spread from cell to cell were removed but without them it has been found that the these disabled viruses could poorly infect tumors.

Dr. Kasahara was one of the first to demonstrate that by making retrovirus vectors that keep their ability to spread from cell to cell, these viruses are much better at infecting tumors. Through the establishment of a translational consortium funded by the National Institute of Health (comprising the University of California, San Francisco, the University of Southern California, and the National Gene Vector Biorepository) the biotech venture, Tocagen Inc., was created to exclusively license this vector technology for further commercial development. Now, after more than 10 years of preclinical development, this gene therapy vector, designated “Toca 511”, is being evaluated in a series of first-in-human Phase I dose-escalation clinical trials conducted at multiple centers throughout the United States for the treatment of patients with recurrent High-Grade Glioma. (www. clinicaltrials.gov: NCT01156584, NCT01470794, NCT01985256).


This gene therapy treatment works by a two-step mechanism: first, as it spreads through the tumor, this virus delivers a ‘pro-drug activator gene’ to the cancer cells, which confers the ability to convert a non-toxic ‘pro-drug’ into an active anti-cancer drug. The patients then take the pro-drug orally as a pill, which converts the pro-drug into the active potent anti-cancer drug. This form of gene therapy forces the brain tumor itself to generate the toxic chemotherapy drug right inside its own cells, a process that Dr. Kasahara likes to call “intracellular chemotherapy”. Because this conversion happens only inside the infected cancer cells, it is more effective than conventional chemotherapy and does not cause adverse side effects on normal organs.

Video: Toca 511 & Toca FC: Proposed Mechanism of Action

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