In vivo Imaging of Adenovirus Transduction and Enhanced Therapeutic Efficacy of Combination Therapy with Conditionally Replicating Adenovirus and Adenovirus-p27

Abstract

Gene therapy is hampered by poor gene transfer to the tumor mass. We previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (#24RGD) and a replicationdefective E1-deleted adenovirus to enhance the efficiency of gene transfer. Mutant E1 expressed by #24RGD enables the replication of replication-defective adenoviruses in tumors when cancer cells are co-infected with both viruses. In this study, gene transfer rates in xenografts tumors were monitored by bioluminescence in cells infected with the replicationdefective adenovirus-luciferase (ad-luc). Tumor masses treated with CRAD + ad-luc showed dramatically stronger and more prolonged luciferase expression than ad-luc-treated tumors and this expression spread through the entire tumor mass without significant systemic spread. Transduction with CRAD + replication-defective adenovirus-p27 increased the expression of p27 by 24-fold versus transduction with ad-p27 alone. Treatment of a lung cancer cell line and of established lung cancer xenografts with CRAD + adenovirus-p27 also induced stronger growth suppression than treatment with either virus alone. These findings confirm the selective replication of E1-deleted adenovirus containing a therapeutic gene due to the presence of mutant E1 produced by #24RGD in tumors. Moreover, this replication increased the therapeutic gene transfer rate and enhanced its antitumor effects. (Cancer Res 2006; 66(1): 372-7)

Combination of vorinostat and adenovirus-TRAIL exhibits a synergistic antitumor effect by increasing transduction and transcription of TRAIL in lung cancer cells

“…In vivo bioluminescence imaging was taken after 10 min with IVIS 100 (Caliper Life Sciences, Hopkinton, MA). 15 Three different sets of experiments were done.…”

Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells

“…This novel strategy has been successfully tested in xenograft tumors. [8][9][10] In this study, we tested the role of RCAd in enhancing RDAd-carried genes expression in cancer cells. Co-injection of RCAd and RDAd significantly enhanced GFP expression in xenograft NCI-H460 tumors (Fig.…”

“…However, the combination significantly increased the therapeutic efficiency due to selective production of large amounts of RCAd and RDAd, wider spread invasion of neighboring cells, and increased transgene expression in tumor mass. [8][9][10] Until now, the combination strategy only tested E1a driven replication of oncolytic adenoviruses and its role in enhancing RDAd production and transgene expression. The role of E1b in the combination strategy has not been tested.…”

Genetic immunotherapy of lung cancer using conditionally replicating adenovirus and adenovirus-interferon-β

“…Furthermore, the tumor-restricted replication of the E1-deleted adenovirus induced a greater and more prolonged production of the therapeutic gene product with strong antitumor effects. 17,18 In contrast to previous experiments, we used the murine lung cancer cell line for this experiment to evaluate antitumor immunity in syngeneic, immunocompetent mice. Can D24 with or without RGD engineered into the fiber knob protein efficiently infect murine cancer cells and induce the replication of cotransduced replication-defective adenovirus?…”