Abstract 1480: Systemic immunotherapeutic efficacy of an immunocytokine, NHS-muIL12, in a superficial murine orthotopic bladder cancer model

Abstract

Abstract Interleukin-12 (IL-12) is one of the most powerful proinflammatory cytokines capable of supporting T and NK cell function, inducing interferon-gamma while driving a TH1 adaptive immune response. Yet, to date, its success as an antitumor agent in many preclinical models has yet to be realized in a clinical setting due to systemic toxicity. Investigators have developed IL-12 delivery systems to maximize deposition of the cytokine directly in the tumor microenvironment that may be the preferred site for IL-12 while mitigating the dose-limiting systemic effects. Here we describe a novel immunocytokine, NHS-IL12, consisting of two molecules of human (hu) or murine (mu) IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). NHS76 recognizes exposed chromatin-DNA often found in human/murine tumors that have outpaced their blood vessels and the inadequate perfusion quickly results in tumor necrosis. Indeed, previous studies have shown selective tumor uptake of NHS-IL12 in necrotic subcutaneous murine tumors. In the present study, we evaluated the use of NHS-muIL12 in a murine orthotopic bladder cancer model (MB49 Luc). MB49 luciferase positive cells, instilled into the bladder form superficial, multifocal tumors which can be monitored in real time with a luciferase-based intravital imaging system. Urothelial bladder cancer is known to respond favorably to immunotherapeutic agents due to the presence of multiple somatic mutations, a high number of TILs, and a response to the live bacterium Bacillus Calmette-Guerin (BCG). NHS-muIL12 was found to be a very potent anti-tumor agent in both subcutaneous and intravesical MB49 tumor models, reducing tumor volume in a dose-dependent manner. For example, in the intravesical bladder model, antitumor effects were initially seen at 2.5 ug/kg administrated as three separate systemic injections. Mice were completely cured of their bladder tumors when treated at 20 ug/kg x 3 NHS-muIL12 injections with durable tumor-free long-term survival. Immune analyses revealed potent p15E-specific CTLs and IFN-γ responses, indicating the development of a specific anti-tumor immune response in mice treated with NHS-muIL12. Underlying the durable tumor-free long-term survival was an immune memory response that protected mice following re-challenge with either subcutaneous or intravesical MB49 tumor cells. Anti-tumor efficacy required the presence of NK or CD8+ T cells as depletion of either abrogated the anti-tumor effects of this agent. NHS-huIL12, is currently being evaluated against solid tumors, in a Phase 1 clinical trial (NCT01417546). We acknowledge the kind contribution of NHS-muIL12 from EMD Serono, Billerica, MA. Citation Format: Amanda J. Vandeveer, Jeffrey Schlom, John W. Greiner. Systemic immunotherapeutic efficacy of an immunocytokine, NHS-muIL12, in a superficial murine orthotopic bladder cancer model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1480.