Abstract A049: Demonstration of systemic antitumor immunity via intratumoral regulated expression of IL-12 in advanced breast cancer and melanoma patients
Authors: Lebel Francois , Barrett John A. , Cai Hongliang , Miao John , Krishnan Suma , Cooper Laurence JN 
Published: May 2016

Abstract
Immunotherapy is an attractive approach to cancer treatment. Localized controlled production of IL-12 in a tumor generates both local and systemic antitumor immune responses. We have developed an adenoviral vector, Ad-RTS-IL-12 (AD), administered intratumorally under control of the RheoSwitch Therapeutic System® (RTS®) expression platform. Gene expression and subsequent IL-12 protein production is tightly controlled by oral administration of the small molecule activator ligand veledimex (AL).
We have shown on mechanism biologic activity and safety with this system in syngeneic mouse studies of melanoma and breast cancer (BC). Those studies demonstrated an AL dose-related increase in tumor IL-12 mRNA and IL-12 protein expression. In addition, a return to baseline IL-12 mRNA and IL-12 protein expression was observed on cessation of AL. These changes correlate with a local and systemic immune and antitumor response.
Subsequently, two open label, phase 2 trials evaluating the safety of inducible IL-12 expression in heavily pretreated subjects with recurrent/metastatic breast or melanoma cancer with surface accessible lesions were performed. The results of these studies showed biologic activity with an acceptable therapeutic index. Treatment with Ad-RTS-hIL-12 + veledimex resulted in an increase in IL-12 and downstream IFN-gamma production and was followed by a rapid increase in IL-10 and IP-10 (indicating IL-12 biologic activity). Tumor lesion results from these two maximum tolerated dose studies are encouraging. In the breast cancer study, 12 subjects were administered Ad-RTS-IL-12 + veledimex. A total of 16 non-injected lesions in 7 breast cancer subjects were evaluated. Of the 16 non-injected lesions, 4 increased in diameter &gt;20%, 6 increased in diameter 0-20% with observed decreases in lesion diameters of 1 lesion 12%, 2 lesions 30-49% and 3 lesions 50-100%. Injected lesions were not evaluated in this study. In the melanoma study, 26 subjects were administered Ad-RTS-IL-12 + veledimex. A total of 70 non-injected lesions in 19 melanoma subjects were evaluated. Of the 70 lesions, 23 increased in diameter &gt;20%, 30 increased in diameter 0-20% with observed decreases in lesion diameters of 7 lesions 10% to 19%, 4 lesions 20-29%, 4 lesions 30-49%, and 3 lesions 50-100%. In the same 19 melanoma subjects, a total of 33 injected lesions were evaluated. Of the 33 lesions, 11 increased in diameter &gt;20%, 9 increased in diameter 0-20% with observed decreases in lesion diameters of 3 lesions 10% to 19%, 1 lesion 25%, 4 lesions 30-49% and 5 lesions 50-100%. Most common ≥ Grade 3 treatment emergent adverse events in BC and melanoma included neutropenia and hyponatremia (16% each), hypotension, cytokine release syndrome, AST increase (11% each), dehydration, fatigue, pyrexia (8% each). All TEAEs and SAEs ≥ Grade 3 reversed rapidly upon discontinuation of veledimex
In conclusion, regulated and controllable IL-12 expression using Ad-RTS-hIL-12 + veledimex in all advanced breast cancer and melanoma patients is promising with an acceptable and rapidly reversible adverse experience profile upon discontinuation of veledimex. The administration of Ad-RTS-hIL-12 + veledimex has shown biologic activity and warrants further clinical investigation.
Citation Format: Francois Lebel, John A. Barrett, Hongliang Cai, John Miao, Suma Krishnan, Laurence JN Cooper. Demonstration of systemic antitumor immunity via intratumoral regulated expression of IL-12 in advanced breast cancer and melanoma patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A049.