Cell Biology: Research & TherapyISSN: 2324-9293

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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: [email protected]
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.

Keywords: Rheoswitch; Gene therapy; Synthetic biology; Cancer models; Controllable expression; IL-12; Cancer immunotherapy; Melanoma

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