Targeting TRAIL Agonistic Receptors for Cancer Therapy

C. Carlo-Stella, C. Lavazza, A. Locatelli, L. Vigano, A. M. Gianni, L. Gianni
2007 Clinical Cancer Research  
Based on preclinical studies demonstrating that tumor necrosis factor^related apoptosis-inducing ligand (TRAIL) exerts a potent and cancer cell^specific proapoptotic activity, recombinant TRAIL as well as agonistic anti^TRAIL-R1and anti^TRAIL-R2 antibodies recently entered clinical trials. Additionally, gene therapy approaches using TRAIL-encoding adenovirus (Ad-TRAIL) are currently being developed to overcome the limitations inherent to TRAIL receptor targeting, i.e., pharmacokinetic of
more » ... cokinetic of soluble TRAIL, pattern of receptor expression, and tumor cell resistance. To optimize gene therapy approaches, CD34 + cells transduced with Ad-TRAIL (CD34-TRAIL + ) have been investigated as cellular vehicles forTRAIL delivery. Transduced cells exhibit a potent tumor killing activity on a variety of tumor cell types both in vitro and in vivo and are also cytotoxic against tumor cells resistant to solubleTRAIL. Studies in tumor-bearing nonobese diabetic/severe combined immunodeficient mice suggest that the antitumor effect of CD34-TRAIL + cells is mediated by both direct tumor cell killing due to apoptosis and indirect tumor cell killing due to vasculardisrupting mechanisms. The clinical translation of cell and gene therapy approaches represent a challenging strategy that might achieve systemic tumor targeting and increased intratumor delivery of the therapeutic agent.
doi:10.1158/1078-0432.ccr-06-2774 pmid:17438088 fatcat:aw4sygw3hbeblncotsr72amba4