44. Phase I Study of Ad5-TRAIL in Men with Clinically Organ Confined Prostate Cancer

Abstract

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4870 We have developed a recombinant adenovirus that encodes human TNF-related apoptosis-inducing ligand (TRAIL; Ad5-TRAIL), which is a potent inducer of tumor cell apoptosis but is not cytotoxic to normal cells. In vitro infection of human prostate tumor cells with Ad5-TRAIL resulted in the rapid transcription and translation of the transferred TRAIL gene into functional TRAIL protein that, when expressed on the cell surface, induced apoptotic death in TRAIL-sensitive prostate tumor cell targets but not normal prostate epithelial cells. Furthermore, in vivo preclinical studies have revealed Ad5-TRAIL can inhibit or slow the outgrowth of human prostate tumor xenografts in SCID mice. Thus, the primary objective of the study is to determine the local and systemic toxicity associated with intraprostatic injection of Ad5-TRAIL delivered in a collagen matrix in men with locally confined prostate cancer, and determine the maximum tolerated dose from four different dose levels. Secondary study objectives will examine the distribution of Ad5-TRAIL within the human prostate after transrectal injection, to determine the effect of transrectal injection of Ad5-TRAIL on existent prostate cancer, and to determine the effect of Ad5-TRAIL-induced apoptosis on immune activation to prostate antigens. Prostate cancer patients (T1c, T2a, T2b and N0, M0) scheduled to undergo radical prostatectomy (RRP) within 10 d following study entry were chosen. The patients had 4 intraprostatic injections of Ad5-TRAIL, 2 per prostate lobe. One week later, endorectal MRI was performed prior to RRP to rule out abscess. Laboratory assessment was performed to assess systemic infection. RRP was then performed if there was no adverse reaction. Operation difficulty was compared to non-injected control patients. Standard histologic evaluation and Gleason grading was performed. Evaluation of the inflammatory infiltrates in Ad5-TRAIL-treated prostates was assessed and compared to control prostate biopsies. To date (11/06), three patients have received the initial vector concentration. There were no immediate or delayed allergic reactions. None of the patients showed abscess on MRI. Operatively, there was no indication of increased inflammation (p=.495), difficulty of the operation, length of stay (p=0.724), or total estimated blood loss. There was no significant increased morbidity post-operatively. All patients had negative margins. Pathologically, each patient had an increase in staging from clinically, and viral vector uptake was shown through visualization of the collagen matrix in the specimen. Ad-5 TRAIL in vivo is known to induce apoptosis in prostate cancer. The initial dose level shows intraprostatic injection is well-tolerated and remains in the prostate after injection. Further increases in dosing will reveal the maximum tolerated dose, and likelihood of increased apoptosis in prostatectomy specimens.