Abstract 536: NBTXR3 potentiate cancer-cell intrinsic interferon beta response to radiotherapy

Abstract

Abstract NBTXR3 represent first in class functionalized radioenhancer optimized for efficient tumor binding and sustained local permanence after intratumoral injection. Recent results of phase III in locally advanced Soft Tissue Sarcoma patients established the significant clinical benefits of NBTXR3 activated by radiation therapy compared to radiotherapy alone. Moreover, preclinical studies using CT26 cells have demonstrated that NBTXR3 activated by RT can induce an anti-tumor immune-response and the abscopal effect. Radiotherapy (RT) can induce T cell-mediated anti-tumor immune responses by multiple mechanisms which include enhancing the recruitment of Batf3-dependent cross-priming dendritic cells (DCs). The latter is contingent on tumor-intrinsic IFN-I induction by cytosolic dsDNA via cGAS/STING pathway, a process that is regulated by the upregulation of Trex1 in a RT dose-dependent fashion (Nat Commun 2017; 8:15618). Here, we utilized the murine TSA breast cancer cell line to test the hypothesis that NBTXR3 strengthens the pro-immunogenic effect of local RT by potentiating tumor cells IFN-I response. For in vitro experiments, TSA cells were exposed to NBTXR3 (800uM) 16 hours prior to RT delivered by a 220-kV source (SARRP) at a dose rate of 283.2 cGy/min. Secreted IFNb in the supernatants was measured by ELISA. Pre-treatment with NBTXR3 enhanced TSA cell radiosensitivity as determined in clonogenic assays. Cell death, as measured by loss of plasma membrane integrity was accelerated by NBTX3 after irradiation of TSA cells with 6 and 8Gy after 24 hours of treatment. NBTXR3 enhanced the secretion of IFNb by irradiated cells. Data suggest that NBTXR3 may enhance the effectiveness of radiation and improve tumor immunogenicity, likely via the induction of IFN-I. The role of the cGAS/STING pathway in the effects of NBTX3 are under investigation in vitro and in vivo. Citation Format: Maria E Rodriguez-Ruiz, Karsten Pilones, Camille Daviaud, Jeffrey Kraynak, Audrey Darmon, Sebastien Paris, Sandra Demaria. NBTXR3 potentiate cancer-cell intrinsic interferon beta response to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 536.