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Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and
Omar D Perez1, Christopher R Logg2, Kei Hiraoka2
1Tocagen Inc, San Diego, California, USA.
Abstract:
Retroviral replicating vectors (RRVs) are a nonlytic alternative to oncolytic replicating viruses as anticancer agents, being selective both for dividing cells and for cells that have defects in innate immunity and interferon responsiveness. Tumor cells fit both these descriptions. Previous publications have described a prototype based on an amphotropic murine leukemia virus (MLV), encoding yeast cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine (5-FC) to the potent anticancer drug, 5-fluorouracil (5-FU) in an infected tumor. We report here the selection of one lead clinical candidate based on a general design goal to optimize the genetic stability of the virus and the CD activity produced by the delivered transgene. Vectors were tested for titer, genetic stability, CD protein and enzyme activity, ability to confer susceptibility to 5-FC, and preliminary in vivo antitumor activity and stability. One vector, Toca 511, (aka T5.0002) encoding an optimized CD, shows a threefold increased specific activity in infected cells over infection with the prototype RRV and shows markedly higher genetic stability. Animal testing demonstrated that Toca 511 replicates stably in human tumor xenografts and, after 5-FC administration, causes complete regression of such xenografts. Toca 511 (vocimagene amiretrorepvec) has been taken forward to preclinical and clinical trials.
Insights
Retroviral replicating vectors (RRVs) offer a novel anticancer strategy by selectively targeting tumor cells. A new vector, Toca 511, demonstrates enhanced genetic stability and potent tumor regression in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Gene therapy for cancer
- Retroviral vector development
Background:
- Retroviral replicating vectors (RRVs) are nonlytic anticancer agents targeting dividing cells with innate immune defects, common in tumors.
- A prototype RRV used murine leukemia virus (MLV) with yeast cytosine deaminase (CD) to convert 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).
Purpose of the Study:
- To select a lead clinical candidate RRV optimizing genetic stability and CD activity.
- To evaluate the efficacy of the selected vector in preclinical cancer models.
Main Methods:
- Vectors were assessed for titer, genetic stability, CD protein and enzyme activity, and 5-FC susceptibility.
- In vivo studies evaluated antitumor activity and vector stability in human tumor xenografts.
Main Results:
- One optimized vector, Toca 511 (T5.0002), exhibited threefold higher specific CD activity and improved genetic stability over the prototype.
- Toca 511 demonstrated stable replication in xenografts and achieved complete tumor regression upon 5-FC administration.
Conclusions:
- Toca 511 (vocimagene amiretrorepvec) is a promising clinical candidate for cancer therapy.
- The optimized RRV shows potential for stable in vivo replication and effective tumor eradication.
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