Synthetic promoters to induce immune-effectors into the tumor microenvironment

• DOI: 10.1038/s42003-021-01664-7
• Publication Date: 2021-01-29T11:19:10Z
• Authors: Yariv Greenshpan; Omri Sharabi; Aner Ottolenghi; Avishag Cahana; Kiran Kundu; Ksenia M. Yegodayev; Moshe Elkabets; Roi Gazit; Angel Porgador
• Keywords: 0301 basic medicine; QH301-705.5; T-Lymphocytes; Breast Neoplasms; Immunotherapy, Adoptive; Proof of Concept Study; Article; Interferon-gamma; 03 medical and health sciences; Mice, Inbred NOD; Cell Line, Tumor; Tumor Microenvironment; Animals; Humans; Biology (General); Promoter Regions, Genetic; Receptors, Chimeric Antigen; Tumor Necrosis Factor-alpha; NF-kappa B; Xenograft Model Antitumor Assays; 3. Good health; Gene Expression Regulation, Neoplastic; Kinetics; HEK293 Cells; Tumor Hypoxia; Female

Abstract Harnessing the immune-system to eradicate cancer is becoming a reality in recent years. Engineered immune cells, such as chimeric antigen receptor (CAR) T are facing danger of an overt life-threatening response due ON-target OFF-tumor cytotoxicity and Cytokine Release Syndrome. We therefore developed synthetic promoters for regulation gene expression under control inflammation Hypoxia-induced signals that associated with tumor microenvironment (TME). termed this methodology chimeric-antigen-receptor-tumor-induced-vector (CARTIV). For proof concept, we studied based on promoter-responsive elements (PREs) IFNγ, TNFα hypoxia; triple PRE-based CARTIV promoter manifested synergistic activity cell-lines potent activation human primary T-cells. platform can improve safety CAR T-cells or other engineered immune-cells, providing TME-focused opening therapeutic window many tumor-associated antigens also expressed by non-tumor healthy tissues.