A novel capsid-modified oncolytic recombinant adenovirus type 5 for tumor-targeting gene therapy by intravenous route

Abstract

Oncolytic adenovirus (Ad)-vectored gene therapy is a promising strategy for cancer treatment. However, the lack of cancer cell selectivity or tumor tissue specificity of Ads limits their clinical application by intravenous (IV) injection. In this paper, a novel recombinant Ad5 vector was constructed carrying the capsid protein IX modified by the tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which targets tumor cells bearing high levels of its receptor far above those of normal cells. Specific association of the Ad virion with TRAIL was achieved using synthetic leucine zipper-like dimerization domains (zippers). Analysis of the chemical properties of the modified recombinant Ad (rAd5pz-zTRAIL-RFP) showed that the TRAIL protein was present on the surface of purified virus particles, and it could induce apoptosis of infected cancer cells prior to expression of foreign genes. We also constructed a novel modified recombinant oncolytic Ad (rAd5pz-zTRAIL-RFP-SΔ24E1a) which showed significantly enhanced anti-tumor effects both in vitro and in vivo by linkage of TRAIL to the viral capsid. Moreover, rAd5pz-zTRAIL-RFP-SΔ24E1a showed significantly improved tumor tissue targeting and reduced liver tropism when IV injected in vivo. Thus, we successfully obtained new oncolytic Ad5 gene therapy vectors with enhanced targeting and efficacy, providing a platform for further clinical application of Ad vectors for cancer treatment.

Enhancing the antitumor activity of an engineered TRAIL-coated oncolytic adenovirus for treating acute myeloid leukemia

“…16,17 A4 showed significant tumor-targeting capability, reduced liver tropism, and potent antitumor activity. 15 However, we also found that the amount of TRAIL coupled with the capsid protein on the viral particle surface was less than expected, indicating that A4 needs to be further improved to ensure better efficacy. Previous studies showed that gene therapy based on either recombinant soluble TRAIL (sTRAIL) or native TRAIL showed selective cytotoxicity toward cancer cells.…”

“…Although A4 showed good targeting and antitumor activity in TRAIL-sensitive breast cancer cells, we found that only~17% of pIX was linked to TRAIL. 15 To enhance AML cell targeting and killing efficacy, we used a new strategy that involved expressing sTRAIL fused to the zipper protein in E. coli, which was termed zTN. Then, zTN was incubated with A4 at 4°C for 16 h. The zTN-coated A4 (named zA4) was purified by density gradient centrifugation (Fig.…”

“…Thus, A4 carries TRAIL on its surface and is able to target tumor cells. 15 TRAIL induces apoptosis by binding the death receptors (DR4 and DR5) that are highly expressed on the surfaces of tumor cells. 16,17 A4 showed significant tumor-targeting capability, reduced liver tropism, and potent antitumor activity.…”

A tropism-transformed Oncolytic Adenovirus with Dual Capsid Modifications for enhanced Glioblastoma Therapy

“…In addition, protein IX (pIX) exposed on the adenoviral capsid also represents an ideal site for insertion of a tumor-targeting ligand at its C terminus [21,22]. In our previous study, we constructed a novel tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-modified oncolytic adenovirus vector, termed A4 [23]. The engineered A4 virus carried the TRAIL gene in its genome and presented the TRAIL protein on the viral surface via a Leu-zipper linkage to pIX [23].…”

“…In our previous study, we constructed a novel tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-modified oncolytic adenovirus vector, termed A4 [23]. The engineered A4 virus carried the TRAIL gene in its genome and presented the TRAIL protein on the viral surface via a Leu-zipper linkage to pIX [23]. TRAIL, a typical member of the TNF superfamily, has been demonstrated in numerous studies to specifically induce cancer cell apoptosis by binding to its receptor, TRAILR1 (also known as DR4) or TRAILR2 (also known as DR5), which contain intracellular death domains [24,25].…”