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ET-60ENHANCED THERAPEUTIC EFFICACY OF PRODRUG ACTIVATOR GENE THERAPY WITH A NON-LYTIC RETROVIRAL REPLICATING VECTOR (TOCA 511) COMBINED WITH RADIATION THERAPY IN EXPERIMENTAL GLIOMA

ABSTRACT: A tumor-selective non-lytic retroviral replicating vector (RRV), Toca 511 (vocimagene amiretrorepvec), is being investigated in clinical trials in patients with recurrent high grade glioma (rHGG) (www.clinicaltrials.gov NCT01156584, NCT01470794, NCT01985256). Toca 511 encodes a modified yeast cytosine deaminase (CD), which converts oral prodrug 5-FC into the anticancer drug 5-fluorouracil (5-FU) within infected tumor cells. Since 5-FU is a radiosensitizer, we investigated in preclinical models the combination of Toca 511, 5-FC and radiation for treatment of human HGG. U87 and radioresistent U87EGFRvIII cells were infected in vitro with Toca 511 and subsequently irradiated with 0, 3, 6 or 9 Gy. In non-irradiated and irradiated cells, RRV infected >95% of cells by day 21 showing that radiation does not perturb viral spread. In vitro clonogenic survival assays showed significant radiosensitization with 5-FC in RRV-infected U87EGFRvIII cells. For in vivo survival studies, U87EGFRvIII cells (5 x 104) were stereotactically implanted into athymic mouse brain and Toca 511 (105 Transducing Units) was injected intratumorally 4 days later. Mice were treated with a single cycle of intraperitoneal PBS or 5-FC (500 mg/kg) for 5 days from day 10 to 14, with or without irradiation (2 Gy/fr/day; total 10 Gy, or 4 Gy/fr/day; total 20 Gy). Mice treated with 20 Gy and a single cycle of 5-FC showed significantly longer survival compared with the other two groups (p<0.0001) and median survival was >75 days. Next, mice were treated with multiple cycles of PBS or 5-FC (intraperitoneal, 5 days every 2 weeks, 5 cycles) with or without irradiation at the lower dose (total 10 Gy). Mice treated with 10 Gy and 5 cycles of 5-FC showed significantly longer survival (p<0.0001) and median survival was >89 days. These efficacy data support clinical investigation of Toca 511 and 5-FC in combination with radiation in the first-line setting for patients with HGG.

SUBMITTER: Takahashi M

PROVIDER: S-EPMC4218156 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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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.

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ET-60ENHANCED THERAPEUTIC EFFICACY OF PRODRUG ACTIVATOR GENE THERAPY WITH A NON-LYTIC RETROVIRAL REPLICATING VECTOR (TOCA 511) COMBINED WITH RADIATION THERAPY IN EXPERIMENTAL GLIOMA

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