Abstract 3647: Treatment of glioblastoma through the controlled localized production of IL-12 by the RheoSwitch Therapeutic System® Platform
Authors: Barrett John A. , Cai Hongliang , Lebel Francois , Meshaw Kay R. , Zmetra Tami , Lewis Jonathan 
Published: May 2015

Abstract
Challenges in developing immunotherapies against glioblastoma include the immune-privileged status of the CNS and the physiological processes that contribute to the suppression of immune responses in the brain. The localized controlled production of IL-12 in the tumor may increase cytotoxic T cell infiltrate and subsequently reduce tumor vascularity and tumor volume, resulting in a prolongation of survival. We have developed an adenoviral vector, Ad-RTS-mIL-12 (AD), administered intratumorally under the control of the RheoSwitch Therapeutic System® (RTS®) expression platform. Gene expression and subsequent IL-12 protein production is controlled by the oral administration of the small molecule activator ligand veledimex (AL). We have shown the the safety and biologic activity of this system in both nonclinical and clinical studies in melanoma and breast cancer. Based upon these favorable results we chose to study the activity of RTS-mIL-12 delivered intratumorally by an adenoviral vector-based approach in an orthotopic murine glioma model. The ability of AL to cross the blood brain barrier was assessed in both naive and orthotopic GL-261 tumor bearing C57B6 mice. The results in mice demonstrated that AL brain tissue levels increased from 25325 to 47868 ng*h/g in naïve mice at doses of 225- 450 mg/m2 p.o. administered on either QD or BID schedules while, as anticipated, the levels of AL in brain tissue increased in the tumor bearing mice. At 450 mg/m2/day BID p.o. increased brain tissue AL levels in GL261 mice increased by approximately 6 fold from 324±51 ng/g in normal mice to 1950±573 ng/g at Day 3 and were sustained through 14 days of continuous dosing (1150±212 ng/g). Based on these findings we assessed the effects of AD + AL on survival in the orthotopic GL261 syngeneic mouse glioma model where each animal received 1 x 105 GL261 glioma cells via intracranial injection on Day 0. In this study AD was administered intratumorally at 1 x 1010 vp/animal on Day 5. AL was administered via gavage at doses of 450-1200 mg/m2/day for 14 consecutive days on a BID schedule. In addition, bevacizumab 30mg/m2 biwkx3 and dexamethasone 6mg/m2/day BID x14 days were studied. AD + AL demonstrated a dose-related increase in survival benefit without exhibiting an adverse safety profile. At Day 100 with (study termination), 45, 50 and 68% of the animals that received doses of 450, 900 or 1200mg/m2/day, respectively, were alive. In contrast, the median survival in the vehicle control groups was 18 days, while in the bevacizumab and dexamethasone groups the median survival was 22 and 24 days, respectively. Additional studies in this model are ongoing to determine the optimal dose and schedule. This novel regulated immunotherapeutic approach could potentially be translated into an effective clinical regimen for the treatment of glioblastoma.
Citation Format: John A. Barrett, Hongliang Cai, Francois Lebel, Kay R. Meshaw, Tami Zmetra, Jonathan Lewis. Treatment of glioblastoma through the controlled localized production of IL-12 by the RheoSwitch Therapeutic System® Platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3647. doi:10.1158/1538-7445.AM2014-3647