447. Replication-Competent Oncolytic Adenovirus Vectors That Express TRAIL and Over-Express ADP

Abstract

Top of pageAbstract The need for new anti-cancer treatments is evident from the fact that malignant neoplasms are the second leading cause of death in the United States and third leading cause of death world-wide. Oncolytic adenovirus (Ad) vectors, which kill cancer cells by harnessing the cytolytic nature of the virus life cycle, are a new class of anti-cancer agents that have been demonstrated to be safe in humans but that have thus far yielded disappointing clinical efficacy results, despite demonstrating efficacy in pre-clinical models. We have constructed several new oncolytic Ad vectors that contain features designed to enhance vector efficacy while maintaining safety. All of our vectors over-express ADP, the viral protein required late in infection for efficient cell lysis and release of progeny virions at the culmination of the infectious cycle. Because our vectors over-express ADP, infected cells are lysed rapidly and progeny virions are released efficiently, which translates into improved cell-to-cell dissemination of the vector. Our vectors are also engineered to express the cancer therapeutic protein tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines that shows specificity for neoplastic cells. TRAIL expression and secretion provides a means of enhancing vector efficacy by providing a way to kill uninfected tumor cells. The TRAIL cDNA was inserted into our vectors such that it would be expressed similarly to ADP, that is, abundant expression late in the infectious cycle. We have shown in cultured cancer cells that our TRAIL-expressing vectors synthesize a large quantity of TRAIL late in the infection and are highly cytolytic to both infected and uninfected cells. TRAIL expression in infected cells leads to apoptosis in nearby uninfected cells and ADP expression results in efficient cytolysis of infected cells. As a safety feature, all of the vectors contain a deletion that eliminates expression of nearly all of the E3 proteins; these proteins function to protect infected cells from the immune system. As an additional safety feature, some vectors also contain deletions within the E1A gene that result in selective replication of the vector in cancer cells because the mutant E1A proteins are no longer able to bind to pRB family members or p300/CBP. The vectors were shown to reduce the growth of Hep3B liver cell tumor xenografts grown in nude mice.