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Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression.

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.

SUBMITTER: Perez OD

PROVIDER: S-EPMC3437576 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression.

Perez Omar D OD Logg Christopher R CR Hiraoka Kei K Diago Oscar O Burnett Ryan R Inagaki Akihito A Jolson Dawn D Amundson Karin K Buckley Taylor T Lohse Dan D Lin Amy A Burrascano Cindy C Ibanez Carlos C Kasahara Noriyuki N Gruber Harry E HE Jolly Douglas J DJ

Molecular therapy : the journal of the American Society of Gene Therapy 20120501 9

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 d ...[more]

PMID: 22547150

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Project description:Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.

Project description:Abstract Toca 511, a clinical-stage retroviral replicating vector (RRV) encoding an optimized yeast cytosine deaminase (CD) prodrug activator gene, in combination with Toca FC (extended-release 5-fluorocytosine (5-FC)), is designed to produce 5-FU which kills cancer cells and immune-suppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long term survival. The combination treatment is currently under evaluation in an international Phase 2/3 trial in patients with recurrent high-grade glioma. In the present study, we investigated the feasibility of further applying Toca 511 to brain-metastatic breast cancer, which frequently arises from highly aggressive, treatment-refractory, “triple-negative” (ER(-) PR(-) HER2(-)) disease, and is associated with a dismal prognosis of 4-6 months survival. We first evaluated in vitro replication kinetics of RRV encoding the GFP reporter gene in MDA-MB-231-BR (human) and JC (murine) breast cancer cells. After virus inoculation at either M.O.I. of 0.01 or 0.1, high levels of transduction were achieved within 1-2 weeks as measured by flow cytometric quantitation of GFP fluorescence. Next, we tested in vitro cytotoxicity by MTS assay after 5-FC treatment of MDA-MB-231BR and JC cells transduced with Toca 511. In both Toca 511-transduced breast cancer lines, cell viability was reduced by approximately 70-85% after exposure to 0.1 mM 5-FC and complete cell killing was observed with 1 mM 5-FC within 4-6 days. In survival studies, animals treated with Toca 511 followed by 5-FC prodrug showed statistically significant (231-BR: p<0.0001, JC: p=0.0003) survival benefit compared to the control group. These data provide preclinical validation for a new Phase Ib trial evaluating RRV-mediated immunotherapy in various types of metastatic malignancies, including CNS-metastatic breast cancer (TOCA 6 trial: clinicaltrials.gov NCT02576665), currently recruiting at the University of Miami.

Project description:Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid derived suppressor cells and tumor associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6–19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting > 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended Ph2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the Phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

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Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression.

Publications

Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression.

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