Abstract B04: Multimodal cancer immunotherapy combining IL-8 inhibition, adenovirus vaccine, IL-15 super agonist, and anti-PD-L1/TGFβRII agent reduces mesenchymalization and enhances anti-tumor efficacy
Authors: Horn Lucas , Hamilton Duane , Maeda Dean , Zebala John , Lee John , Rabizadeh Shahrooz , Jones Frank , Soon-Shiong Patrick , Su Zhen , Schlom Jeffrey , Palena Claudia 
Published: June 2021

Abstract
Tumor cells utilize the secretion of proinflammatory cytokines and chemokines and the surface expression of inhibitory ligands to promote an immune-suppressive tumor microenvironment that facilitates tumor growth and metastasis. The overexpression of IL-8, TGF-β, PD-L1, the IL-8 receptors CXCR1 and CXCR2, as well as numerous other factors by various solid and hematologic cancers are major obstacles in the promotion of a strong and effective antitumor immune response. Both IL-8 and TGF-β have been identified as key potentiators of tumor cell plasticity and the acquisition of mesenchymal features by epithelial cancer cells, i.e., mesenchymalization, which increases metastatic dissemination. Both IL-8 and TGF-β can also promote tumor angiogenesis, myeloid-derived suppressor cell (MDSC) function in the tumor microenvironment, and resistance to immune-mediated killing. Additionally, tumor cell expression of PD-L1 inhibits effective T-cell responses at the tumor site. Here we report the use of a systematic and rational multimodal cancer immunotherapy approach that combines induction of T cell potentiation through an IL-15 super agonist and adenoviral cancer vaccine with inhibition of three immunosuppressive pathways through blockade of IL-8, TGF-β, and PD-L1. Combination of the novel small-molecule inhibitor SX-682 that irreversibly binds and blocks both CXCR1 and CXCR2 with an adenoviral-based cancer vaccine, N-IL15 (previously designated ALT-803), and the anti-PD-L1/TGFβRII agent, M7824, significantly delayed tumor growth in murine models of breast and colon cancer. Mechanistic studies demonstrated that this multimodal combination therapy was able to markedly increase tumor infiltration with CD4+ and CD8+ T cells, including central memory and effector memory subsets, and to decrease infiltration with Ly6G+/Ly6C- MDSC. Studies with SX-682 as a monotherapy suggest that CXCR1/2 inhibition reduces migration rates of Ly6G+/Ly6C- MDSC (CXCR2+). Studies with models of claudin-low, mesenchymal-enriched, human triple-negative breast cancer demonstrated that CXCR1/2 inhibition was also effective at promoting a switch from a mesenchymal to an epithelial tumor phenotype, while simultaneously enhancing the tumor cells’ susceptibility to immune-mediated cytotoxicity. Our results provide rationale for the future evaluation of this multimodal therapy in the clinic.
Citation Format: Lucas Horn, Duane Hamilton, Dean Maeda, John Zebala, John Lee, Shahrooz Rabizadeh, Frank Jones, Patrick Soon-Shiong, Zhen Su, Jeffrey Schlom, Claudia Palena. Multimodal cancer immunotherapy combining IL-8 inhibition, adenovirus vaccine, IL-15 super agonist, and anti-PD-L1/TGFβRII agent reduces mesenchymalization and enhances anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B04.