Adeno-Associated Viral Vectors Penetrate Human Solid Tumor TissueIn VivoMore Effectively than Adenoviral Vectors

Abstract

The transduction efficiencies of adeno-associated viral vectors (AAV, serotype 2) and adenovirus vectors (ADV, serotype 5) were examined in three different models of cancer. First, we used flow cytometry to quantitate AAV-GFP or ADV-GFP transduction in 13 cell lines derived from malignant tissue (6 gliomas, 6 mammary cancers, and 1 leukemia). These experiments showed variable transduction efficiency (0%-81%) between the cell lines, with ADV being more effective compared to AAV in 9 of 13 cell lines. Second, spheroids prepared from human glioblastomas were infected with ADV or AAV expressing GFP or lacZ cassettes, and after 2 weeks, uniform reporter gene expression was observed on the spheroid. Whereas AAV produced consistent transduction throughout the spheroids, ADV infection was mainly limited to the outer cell layers of the spheroids, suggesting that AAV were more efficient at penetrating solid tumor tissue. Third, human biopsies from glioblastoma multiforme patients were xenografted into nude rats and grown for 4 weeks followed by viral vector injection. Combined use of high-resolution magnetic resonance imaging (MRI) and histologic analysis allowed the identification of transduced cells and their spatial distribution within the tumors. AAV-mediated transgene expression was observed in cell clusters through the entire tumor, while ADV-mediated transduction was restricted to cells at the tumor periphery. Thus, while AAV and ADV vectors may infect tumor-derived cell lines to a similar degree, AAV penetrated glioblastoma spheroids and xenografts more efficiently compared to ADV vectors. These results suggest that AAV may be suitable for therapeutic gene delivery to malignant tumors.

Recombinant adeno‐associated virus (rAAV) expressing TFPI‐2 inhibits invasion, angiogenesis and tumor growth in a human glioblastoma cell line

“…Several studies have concluded that gene transfer to solid tumors is a limiting factor in gene therapy. [36][37][38][39][40] Enger et al 41 have shown that tumor spheroids infected with rAAV-lacZ efficiently penetrated and transduced within the central regions as compared to spheroids infected with an adenovirus carrying the lacZ gene. These observations were consistently observed in spheroids from different tumors and with increasing concentration of viral particles.…”

AAV-encoded expression of TRAIL in experimental human colorectal cancer leads to tumor regression

“…5,6 Recombinant AAV has been shown to direct long-term transgene expression without giving rise to host toxicities or serious cellular immune responses to various tissues, including certain tumor types. 1,7 Enger et al 8 found that it better disseminates through tumors in vivo and consequently transduces cells more efficiently than the larger adenovirus. In the light of long-term expression achieved with rAAV, it is not only suited to deliver acutely acting cellular suicide genes, but could also be used to produce tumoricidal proteins systemically or locally that could act on residual disease after surgery and/or chemotherapy.…”

Recombinant adeno‐associated virus‐mediated TRAIL gene therapy suppresses liver metastatic tumors

“…16 Recently, recombinant AAV vector (rAAV)-mediated gene delivery has emerged as a safe and efficacious approach for human cancer gene therapy. 17 Long-term gene expression using rAAV as delivery vehicles has been achieved in various tissues without evoking host toxicities or serious cellular immune responses. TRAIL expressed from a rAAV vector has been shown to block outgrowth of human colorectal tumors grown in mice.…”