Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy

Abstract

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.

TRAIL-secreting mesenchymal stem cells promote apoptosis in heat-shock-treated liver cancer cells and inhibit tumor growth in nude mice

“…25 Far smaller tumors were detected in nude mice in the T-MSC/HS-N1-S1 group than in mice in the T-MSC/N1-S1, V-MSC/HS-N1-S1, L02/HS-N1-S1, and PBS/HS-N1-S1 groups. (B) Survival curve of subcutaneous liver cancer-bearing nude mice.…”

“…20 Such measures have involved combining RFA with Ad-stTRAIL, 9 lysothermosensitive liposomal doxorubicin, 5-FU, 21 IL-7, IL-15, 22 endostatin 23 , and radiotherapy. 24 Ad-stTRAIL 25 and lysothermosensitive liposomal doxorubicin 26 have entered phase I clinical trials. In the present work, the conditions of the RFA transition zone were simulated with heat treatment (43 1C for 45 min) in the cultured cells.…”

Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model

“…In a landmark human GBM in vivo experiment, 10 % of glioma cells were transduced 2 days after intratumoral administration of Ads, a high transduction efficiency compared to the almost negligible levels seen for retroviral transduction of the same tumor type [64]. Gene therapy approaches using adenoviral vectors for the treatment of GBM have been tested in recent clinical trials and involve the delivery of conditionally cytotoxic genes [72,73], soluble pro-apoptotic cytokines [74], or oncolytic adenoviral vectors [75,76]. In addition, this approach has a powerful bystander effect which involves: 1) the release of Flt3L from infected tumor cells that reach the systemic circulation and stimulates the expansion and recruitment of immune cells involved in the anti-tumor immune response, 2) TK-phosphorylated GCV that can be transported from infected cells to neighboring tumor cells through gap junctions, amplifying the cytotoxic effect of Ad.TK, 3) the anti-tumor immune response triggered by this treatment can detect and kill tumor cells spread throughout the normal brain parenchyma.…”

Go Green: The Anti-Inflammatory Effects of Biliverdin Reductase

“…Both enzymes catalyze reduction of a double-bond between the pyrrole ring into a single-bond using NADH or NADPH as electron donors dependent on a pH optima (6.75 and 8.7, respectively; McCoubrey et al, 1995). BR and BV, through BVR have been shown to prevent cellular senescence (Kim et al, 2011) and apoptosis (Jansen et al, 2010). Regulation of HO-1 and BVR expression and their enzymatic activity is critical for function of the heme degradation pathway.…”