Research Article, Cell Biol Henderson Nv Vol: 5 Issue: 2
A Synthetic Biology Rheoswitch Therapeutic System® for the Controlled Local Expression of IL-12 as an Immunotherapy for the Treatment of Cancer
| Barrett JA1*, Cai H1, Miao J1, Sun L1, Murugesan S2, Chan T2, Chakiath M2, Krishnan S2, Einstein R2, Lebel F1 and Cooper LJN1 | |
| 1ZIOPHARM Oncology, Boston, Massachusetts, USA | |
| 2Intrexon Corp, Germantown, Maryland, USA | |
| Corresponding author : JA Barrett
ZIOPHARM Oncology, Boston, Massachusetts, USA Tel: 617-259-1970 E-mail: JABarrett@ziopharm.com |
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| Received: August 30, 2016 Accepted: September 07, 2016 Published: September 13, 2016 | |
| Citation: Barrett JA, Cai H, Miao J, Sun L, Murugesan S, et al. (2016) A Synthetic Biology Rheoswitch Therapeutic System® for the Controlled Local Expression of IL-12 as an Immunotherapy for the Treatment of Cancer. Cell Biol (Henderson, NV) 5:2. doi:10.4172/2324-9293.1000126 |
Abstract
Tumors escape the immune system through the process of immunoediting. Restoration of the immune system’s ability to detect the tumor should result in improved therapeutic outcome. A gene delivery platform technology, RheoSwitch Therapeutic System® (RTS®), has been developed to enable the controlled, regulated expression of a target gene which locally delivers the desired therapy to patients. A replication-incompetent adenoviral vector, administered intratumoral, is engineered to express IL�??12 (Ad-RTS-IL-12) under control of the RheoSwitch Therapeutic System, where IL-12 expression is controlled via the administration of an oral activator ligand (veledimex). In the presented preclinical studies we have demonstrated that the oral administration of veledimex resulted in a dose-related increase in tumor veledimex levels. The increase in tumor veledimex levels in combination with Ad-RTS-mIL-12 resulted in a dose-related increase in the IL-12 mRNA (switch on) leading to dose-related increases in IL-12p70 in the tumor with minimal increase in serum IL-12. The increase in tumor IL-12 correlated with an increase in tumor CD8+ cytotoxic T cells and a concomitant decrease in regulatory T cells (Tregs) in the tumor microenvironment. Importantly, Ad-RTS-mIL-12 + veledimex elicited dose-related decreases in tumor growth rate with no significant change in body weight in both breast and melanoma syngeneic mouse models. When veledimex was discontinued, expression of IL-12 mRNA returned to baseline concomitant with tumor IL-12 levels. In summary, these results highlight the potential of a synthetic biology-based approach for cancer treatment, safely leveraging the full anticancer potential of some immunomodulators without the serious side-effects associated with systemic injection.
