Abstract B298: The controlled local expression of IL-12 as an immunotherapeutic treatment of glioma through the use of the Rheoswitch Therapeutic System® (RTS®) platform.

Abstract

Abstract The challenges of developing immunotherapies to treat glioma include the immune- privileged status of the CNS and the physiological processes that contribute to the suppression of immune responses in the brain. The paucity of dendritic cells (DC) in the brain combined with lack of lymphatic drainage, the production of inflammatory mediators, and the physical blood-brain barrier provide several challenges in eliciting tumor specific responses. We have previously assessed the safety and biologic activity of two different RheoSwitch Therapeutic System® (RTS®) controlled IL-12 expression-based therapeutic candidates in Phase I clinical trials for the treatment of metastatic melanoma: AD-RTS-hIL-12 (AD) and DC-RTS-hIL-12 (DC), along with the activator ligand veledimex, also known as INXN 1001 (AL). Based upon preliminary favorable results observed for these two product candidates, we chose to study the activity of RTS-mIL-12 delivered intratumorally by either a dendritic cell or an adenoviral vector-based approach in an orthotopic murine glioma model. The ability and the extent of AL to cross the blood brain barrier (BBB) were assessed in both C57B6 mice and cynomolgus monkeys. The results in mice demonstrated that AL crosses the BBB (peak and trough level of 67-16 ng/mL in cerebral spinal fluid (CSF) over the dose range of 450-900 mg/m2/day) which exceeded tumor AL levels previously shown to induce the production of mIL-12 and resulted in a >50% tumor growth inhibition in the 4T1 mouse model. AL also crossed the BBB in a similar fashion in the cynomolgus monkey. The effects of DC and AD on survival were assessed in the mouse orthotopic GL261 glioma model where each animal received 1 x 105 GL261 glioma cells via intracranial injection (i.c.) on Day 0. In this study murine dendritic cells were transduced at increasing multiplicity of infection (MOI) of 100, 500, 1,000, 5,000, or 10,000 of AD vector particles (vp)/cell. The transduced DC's were intratumorally (i.t.) administered at 1 x 106 DC /animal, on Day 5. AD was administered i.t. at 1 x 108, 5 x 108, 1 x 109, or 5 x 109 vp/animal on Day 5. AL was administered ad libitum in the chow starting on Day 4 (∼675 mg/m2/day) and continued for the duration of the study. DC + AL or AD + AL both clearly demonstrated a dose-related increase in survival benefit without exhibiting an adverse safety profile. All animals treated with DC > 5000 MOI + AL or AD 5 x 109 vp + AL survived throughout the duration of the study (100% survival at 75 days) with no adverse clinical signs observed. In contrast, the mean survival in the control groups was 22 ± 3 days. 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 glioma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B298. Citation Format: John A. Barrett, Lei Sun, Charles Reed, Laurent Humeau, Francois Lebel, Beth A. Hollister, Kay R. Meshaw, Jon Lewis. The controlled local expression of IL-12 as an immunotherapeutic treatment of glioma through the use of the Rheoswitch Therapeutic System® (RTS®) platform. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B298.