A Synthetic Biology Rheoswitch Therapeutic System® for the Controlled Local Expression of IL-12 as an Immunotherapy for the Treatment of Cancer

Posted on Updated on

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.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s