Abstract
Clinical application of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based cancer therapeutics has not reached optimal potencies in part due to inadequate drug stability and inefficiencies in cancer-selective drug delivery. As such, innovative strategies regarding drug design and delivery are of utmost importance to achieve improved treatment results. With our current study, we aimed at exploring the groundwork for a two-stage targeting concept, which is based on the intrinsic tumor homing capacity of mesenchymal stem cells (MSCs) as cellular drug factories for the in situ production of our newly designed and biomarker-targeted TRAIL-based TR3 therapeutics. Since MSCs are primary cells, capable in vitro of only a limited number of cell divisions, identification of suitable strategies for their efficient genetic manipulation is of critical importance. We chose adenoviral (Ad) vectors as a transduction vehicle due to its ability to infect dividing and non-dividing cells and because of their limited restrictions regarding the packaging capacity of their genetic payload. In order to enhance the transduction efficacy of MSCs using Ad5 wild-type-based vectors, we tested a variety of fiber knob modifications on a panel of patient-derived MSC lines established from adipose tissue. We identified Ad5pK7, an Ad5 vector containing a polylysine fiber knob modification, exhibiting the highest transduction rates across a panel of 16 patient-derived MSC lines. We further demonstrated that MSCs could be efficiently transduced with an Ad5pK7 vector containing membrane-anchored and secreted TR3 expression units, including the MUC16 (CA125)-targeted variant Meso64-TR3. In both in vitro and in vivo experiments, MSC-derived Meso64-TR3 was far more potent on MUC16-expressing ovarian cancer compared to its non-targeted TR3 counterpart. Our findings thus provide the foundation to initiate further preclinical investigations on MSC-mediated treatment options in ovarian cancer using biomarker-targeted TR3-based biologics.
Highlights
Ovarian cancer causes more deaths than any other cancer of the female reproductive tract, and at best, 5-year survival rates are approximately 46% [1, 2]
Endogenous, native Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) self-assembles into three non-covalently associated homotrimers at the plasma cell membrane to become biologically active with the amino-termini (N-termini) of the individual protomers pointing to the cytoplasm of the cell (Fig 1A, left panel, type-II membrane protein)
The resulting stoichiometry with only one N- and one C-terminus per trimer represents a characteristic feature of all TR3-based biologics, whereas trimers based on wild-type TRAIL contain three N- and C-termini each, respectively
Summary
Ovarian cancer causes more deaths than any other cancer of the female reproductive tract, and at best, 5-year survival rates are approximately 46% [1, 2]. Efficient delivery of novel systemically administered cancer therapeutics remains an important challenge in drug development, especially within the field of gynecologic oncology. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anti-cancer therapeutic due to its ability to induce apoptosis upon binding to its death receptors DR4 and DR5 [3,4,5,6,7,8]. Since the first report describing TRAIL in 1995 [5], the majority of research has explored this molecule as an anti-cancer therapeutic, capitalizing on its ability to selectively induce apoptosis in a broad range of tumor cell lines with minimal effect on normal cells [4, 5, 9]. Major challenges utilizing conventional TRAIL in clinical practice include possible off-target toxicity in the liver and brain [10, 11] and rapid clearance from the body with a half-life of approximately one hour [12], requiring repeated injections to maintain high enough concentrations to achieve potential therapeutic responses [13]
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