Abstract
Cellular therapies based on mesenchymal stromal/stem cells (MSC) are promising strategies in regenerative medicine and oncology. Despite encouraging results, there is still some level of concerns on inoculating MSC in cancer patients. To face this issue, one possibility resides in engineering MSC by incorporating a suicide gene in order to control their fate once infused. Strategies based on Herpes Simplex Virus Thymidine Kinase (HSV-TK) and the Cytosine Deaminase genes have been developed and more recently a novel suicide gene, namely, iCasp9, has been proposed. This approach is based on a variant of human Caspase9 that binds with high affinity to a synthetic, bioinert small molecule (AP20187) leading to cell death. Based on this technology so far marginally applied to MSC, we tested the suitability of iCasp9 suicide strategy in MSC to further increase their safety. MSC have been transfected by a lentiviral vector carrying iCasp9 gene and then tested for viability after AP20187 treatment in comparison with mock-transfected cells. Moreover, accounting our anti-tumor approaches based on MSC expressing potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), we generated adipose MSC co-expressing iCasp9 and TRAIL successfully targeting an aggressive sarcoma type. These data show that anti-cancer and suicide mechanisms can coexist without affecting cells performance and hampering the tumoricidal activity mediated by TRAIL. In conclusion, this study originally indicates the suitability of combining a MSC-based anti-cancer gene approach with iCasp9 demonstrating efficiency and specificity.
Highlights
Mesenchymal stromal/stem cells (MSC) are a heterogeneous population of fibroblast-like cells originallyEmilia, Modena, Italy 4 Technopole of Mirandola TPM, Modena, Italy 5 Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA isolated from bone marrow and other tissues including adipose tissue, peripheral blood, umbilical cord blood, and Wharton’s jelly, among others [1, 2]
This latter possibility gained a relevant interest in the last decade and we and others have been developing anti-tumor approaches based on MSC expressing the potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), variants demonstrating efficacy against several tumors [7–9, Spano et al, Submitted]
Dose-response assay showed that the addition of B/B Homodimerizer efficiently triggers apoptosis in both ADMSC iCasp9 and Adipose-derived MSC (AD-MSC) TRAIL-iCasp9 (Fig. 1)
Summary
Growing evidences revealed that MSC retain unique immunological features that are relevant for the treatments of immune-related disorders [5] and for their possible use as cellular vehicles to deliver bioactive molecules inside tumor parenchyma and stroma [6]. One possibility to face these possibilities is to incorporate a suicide gene in MSC; the most commonly used are the Herpes Simplex Virus Thymidine Kinase and the Cytosine Deaminase [11] These transgenes confer the ability to convert a non-toxic prodrug into an active cytotoxic compound that kills the cell itself and the neighbors. Additional drawbacks may come from the limitation in concurrent administration of drugs (i.e., Ganciclovir) that, delivered for a possible CMV-viral infection, can lead to unintended elimination of gene-modified cells [15]; further evidences indicate the possible onset of drug resistance on target cells [16]
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