Toca 511, the key novel component of Tocagen’s first Product Candidate (Toca 511 & Toca FC), was developed using the breakthrough RRV technology that allows selective targeting of cancer cells and a selective, local and systemic antitumor immune response without off-target toxicity. Toca 511 is used in combination with Toca FC, a novel extended-release tablet containing 5-FC (flucytosine).
Our Preclinical Studies
Preclinical data indicate that Toca 511 can hide in the cancer environment and spread from cancer cell to cancer cell, thereby allowing targeted delivery of a potent anticancer drug selectively to the cancer tissue while leaving healthy tissue unharmed. In addition to the direct killing of cancer cells, we believe that the immune system is selectively activated by the local tumor killing, with resultant systemic anti-tumor immunity.
Toca 511 is specifically designed to deliver the genetic instructions to produce Cytosine Deaminase (CD) protein inside cancer cells. The CD enzyme then catalyzes the conversion of the antifungal drug 5-FC (flucytosine) to the anticancer agent 5-FU (5-fluorouracil) inside the cancer cells. Thus the CD protein enables local production of a powerful, FDA approved anticancer drug (5-FU) that selectively destroys the cancer cells.
This targeted gene delivery strategy may result in higher local concentrations of the cytotoxic drug 5-FU and its phosphorylated metabolites in the cancer cells than would be otherwise attainable under currently accepted treatment regimens. This is because 5-FU has a narrow therapeutic index and when administered systemically, it exhibits dose-limiting toxicity to the rapidly dividing cells of the GI tract and bone marrow. Yet 5-FU has a very short half-life and is rapidly cleared. Additionally, 5-FU does not readily cross the blood brain barrier thereby further limiting the concentration of drug that can be delivered to cancer cells in the brain.
In multiple preclinical models of brain cancer, the animals treated with Toca 511 and 5-FC demonstrated statistically significant prolonged survival compared to control (non-treated and Toca 511 alone treated) animals. The control groups showed a median survival of approximately 1 month, compared to prolonged survival in the Toca 511 and 5-FC treated animals. In experiments extended out to one year, almost all mice treated with Toca 511 and 5-FC remained alive. No significant toxicity was observed in the animals treated with Toca 511 and 5-FC.
In similar experiments as shown above conducted in immune deficient and immune competent mice, tumors recur after stopping 5-FC treatment in immune-deficient, but not in immune-competent animals. This suggests that the immune system is able to control any residual tumor following treatment with 5-FC in syngeneic mice with an intact immune system, resulting in long-term survival.
Furthermore, as shown below, animals that had long-term survival from their brain cancer treatment with Toca 511 and 5-FC and subsequently re-challenged with the same tumor administered to their flank region were able to resist tumor growth. In contrast, animals not previously challenged and treated, allowed extensive brain tumor growth in their flank region.
Finally, if PBMC are taken from syngeneic mice successfully treated for their tumor and the T cells exposed to tumor in vitro then stained for reactivation (an ELISpot assay for IFN gamma production) many more positives are observed in the cured mice compared to naïve mice. Thus memory T lymphocytes (T cells) remain active against gliomas previously treated with Toca 511 & 5-FC in mice that are in 1 year remission (see below).
The preclinical studies conducted to date have supported our ongoing clinical trials evaluating Toca 511 in combination with Toca FC in patients with recurrent high grade glioma (HGG), including recurrent Glioblastoma Multiforme (GBM) and recurrent anaplastic astrocytoma.
We believe these clinical trials may allow for early conceptual validation of our RRV platform. In the future, Tocagen is considering additional studies of Toca 511 & Toca FC in patients with high grade glioma in the first line (primary) setting, and in patients with cancers that have metastasized to the brain, liver and lung from other advanced cancers including breast, lung, colorectal, prostate and melanoma.
Brain Cancer (High Grade Glioma)