Targeting TRAIL agonistic receptors for cancer therapy.
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-R1 and 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 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 for TRAIL 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 soluble TRAIL. 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 vascular-disrupting 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.
Carlo-Stella
Carmelo
C
Cristina Gandini Medical Oncology Unit, Istituto Nazionale Tumori, Milan, Italy.
Lavazza
Cristiana
C
Locatelli
Alberta
A
Viganò
Lucia
L
Gianni
Alessandro M
AM
Gianni
Luca
L
D017209:Apoptosis; D004249:DNA Damage; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D016159:Tumor Suppressor Protein p53