Abstract LB-126: Nanoparticle-incorporated STING activator as an immunotherapeutic for PD-L1 resistant triple-negative breast cancer
Authors: Cheng Ning , Watkins-Schulz Rebecca , Junkins Robert , David Clément , Johnson Brandon M. , Montgomery Stephanie A. , Peine Kevin J. , Darr David B. , Yuan Hong , McKinnon Karen P. , Liu Qi , Miao Lei , Huang Leaf , Bachelder Eric M. , Ainslie Kristy M. , Ting Jenny P-y 
Published: August 2018

Abstract
Current immune checkpoint inhibitors (eg. PD-L1) shows limited efficacy for varies cancer types, especially the difficult-to-treat triple-negative breast cancer. This study uses liposomal nanoparticles (NPs) to deliver the STING agonist, cGAMP, as an alternative approach to amplify innate immune activation and anti-tumor treatment. We studied the impact of cGAMP-NPs on macrophage reprograming and activation by determining M1/M2 biomarkers on polarized M2(+) cells and cytokines from secreted supernatants. The critical role of STING/IFNAR signaling in cGAMP-NP-mediated response was also examined. The efficacy was further evaluated in an orthotopically-transplanted model (C3(1)Tag model) for basal-like triple-negative breast cancer (TNBC) and a spontaneous genetic engineered mouse (GEM) model of basal-like TNBC (C3(1)Tag GEM). Both of these preclinical models that are resistant to PD-L1 checkpoint blockade and most other therapies, which parallels TNBC in humans. cGAMP-NPs were shown to activate STING and induce both innate and adaptive host immune responses. Also, cGAMP-NPs accumulated within macrophages at the tumor site and reversed a pro-tumorigenic microenvironment. Effective tumor suppression was achieved by intravenous delivery in orthotopic and GEM of TNBC with no responsivity to anti-PD-L1 and in B16F10 melanoma with limited responsivity to anti-PD-L1. The anti-tumor immunity was achieved in a STING-dependent fashion that relies on T cells and macrophages but does not require prior knowledge of the tumor antigen. cGAMP-NPs were shown to induce M2-like macrophages to skew towards a M1-like phenotype, cytokine production, MHC and co-stimulatory molecule expression, enhanced CD4+ and CD8+ T cells infiltration, and tumor apoptosis. Moreover, cGAMP-NPs alone induced durable anti-tumor T cell responses and prevented the formation of secondary tumors. We demonstrated the amplified efficacy of liposome formulation relative to soluble cGAMP as an anti-tumor therapeutic that obviates the need of intratumoral injection. Our data suggested that cGAMP-NPs are a potent treatment regimen to modulate the microenvironment of tumors with limited or no responsivity to anti-PD-L1.
Citation Format: Ning Cheng, Rebecca Watkins-Schulz, Robert Junkins, Clément David, Brandon M. Johnson, Stephanie A. Montgomery, Kevin J. Peine, David B. Darr, Hong Yuan, Karen P. McKinnon, Qi Liu, Lei Miao, Leaf Huang, Eric M. Bachelder, Kristy M. Ainslie, Jenny P-y Ting. Nanoparticle-incorporated STING activator as an immunotherapeutic for PD-L1 resistant triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-126.