Combined Direct Intratumoral Adenoviral Delivery And Production Of Rheoswitch (R)-Regulated Il-12 And Ifn Alpha Enhances Antitumor Activity In Lung And Breast Cancer Models

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Current cancer immunotherapies have provided limited success in the clinic and innovative strategies are required to further enhance the effectiveness of an anti-tumor immune response.This study assessed anti-tumor activity utilizing intratumoral (i.t.) administration of adenovirus (Ad) with the novel Rheoswitch Therapeutic System®(RTS®), an inducible promoter system, for regulated expression of murine IL-12 or IFNα. Oral administration of a small molecule activator ligand (AL), INXN-1001, regulates the expression of IL-12 in Ad-RTS-mIL-12 and IFNα in Ad-RTS-mIFNα. The regulated expression and therapeutic benefit of IL-12 and IFNα from i.t. administered Ad-RTS-mIL-12 and Ad-RTS-mIFNα, either alone or in combination, was examined in syngeneic Lewis lung carcinoma (LLC) and syngeneic mammary carcinoma (4T1) models. In the LLC model, daily treatment with oral AL alone (administered in feed at 1000 ppm, representing a daily dose of ∼225 mg/kg/day) or i.t. cytokine gene therapy in the absence of AL did not result in significant inhibition of tumor growth compared to control, untreated tumors. In contrast, i.t. injection with 1010 vp Ad-RTS-mIL-12 or Ad-RTS-mIFNα and daily oral AL led to significant tumor growth inhibition by day 25 (72 and 71%, respectively; p<0.05). Notably, combined treatment of the LLC tumors with Ad-RTS-mIL-12 and Ad-RTS-mIFNα with oral AL resulted in significant anti-tumor effect compared to either treatment alone (97% growth inhibition; p<0.05) without overt toxicity as assessed by no change in body weight. In the 4T1 model, i.t. treatment with 1010 vp of Ad-RTS-mIL-12 plus AL or Ad-RTS-mIFNα plus AL led to 58 and 53% inhibition of tumor growth compared to control untreated tumors by day 34 (p<0.05). Notably, concomitant treatment with both Ad-RTS-mIL-12 plus AL and Ad-RTS-mIFNα plus AL resulted in enhanced anti-tumor activity with 80% growth inhibition. These data indicate that the combined treatment strategy using RTS-regulated IL-12 and IFNα in Ad vectors concomitant with AL induces effective therapeutic activity against aggressive murine tumors. Future studies will investigate the mechanism by which both IL-12 and IFNα exert their anti-tumor effect in the above tumor models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1546. doi:1538-7445.AM2012-1546