Abstract 3274: LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model

Abstract

Abstract Liver cancer is estimated to be the third most common cause of cancer-related mortality worldwide in both sexes. Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer in which potential curative surgical options are limited and overall survival poor. Hence, there is an unmet need for new and improved therapies. LTX-401 is a novel oncolytic compound with potent antitumor properties. Owing to its amphiphatic nature, LTX-401 may affect the integrity of cancer cell membranes and induce rapid cell death. Transmission electron microscopy indeed revealed a necrotic cell death phenotype accompanied by massive vacuolization of the cytoplasm and dilated mitochondria. Additionally, LTX-401 induces features of immunogenic cell death (ICD) as seen by the extracellular release of ATP and HMGB1, as well as the mitochondrial DAMP cytochrome C. The antitumor effects of LTX-401 has been explored in an experimental model of hepatocellular carcinoma (JM1 model) using immunocompetent rats. When injected into subcutaneously established lesions, the majority of animals went into remission followed by systemic protective immune responses. Additionally, LTX-401 could affect the growth of distal tumor deposits simulating metastases, hence indicating immune-mediated abscopal responses. Intratumoral treatment of orthotopic liver tumors resulted in cure of approximately half of the animals treated, which later displayed protection against subcutaneous tumor (re)challenge. Splenocytes harvested from immunized animals produced significantly larger amounts of IFN-y when stimulated with tumor cells ex vivo, indicating the presence of tumor-specific (memory) T cells. Histological examinations revealed that LTX-401 caused massive hemorrhagic tumor necrosis, both in subcutaneous and intrahepatic compartments, followed by increased infiltration of T cells. Taken together these results indicate that oncolytic compounds generate an immunogenic tumor environment and may be therapeutically exploited as a novel antitumor and immunotherapeutic approach in HCC. Citation Format: Brynjar Mauseth, Ketil Camilio, Ji-Hua Shi, Øystein Rekdal, Baldur Sveinbjørnsson, Pål-Dag Line. LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model [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 3274.