Abstract 5128: Induction of immunogenic cell death and tumor regression in murine animal models by a novel cytolytic compound, LTX-401

Abstract

Abstract LTX-401 is a de novo designed cytolytic compound that shares many chemical features with anticancer peptides, such as amphipathicity, hydrophobicity and overall net charge. In vitro cytotoxicity studies revealed that LTX-401 was highly active against a panel of malignant cells including murine and human cancer cell lines while displaying selectivity towards human red blood cells. Furthermore, LTX-401 was found to induce immunogenic cell death as demonstrated by the release of Damage-Associated Molecular Pattern molecules, or ‘danger signals’, such as High-Mobility Group Box-1 protein, ATP and cytochrome c. Flow cytometric and confocal microscopy studies also demonstrated reduced signal from lysosomal dye Lysotracker-DND-26, hence indicating loss of lysosomal integrity upon induction of cell death. The latter was supported using transmission electron microscopy, showing distinct morphological characteristics of necrosis. Moreover, at low concentrations, LTX-401 selectively enriched in the Golgi apparatus and initiated a lethal signaling event that in part could be inhibited by Brefeldin A. Complete tumor regression has been obtained in several rodent models, including the B16 mouse melanoma model and the JM1 rat hepatocellular carcinoma model by intratumoral injection with LTX-401. Additionally, previously cured animals showed protection against rechallenge with live tumor cells, indicating the induction of tumor-specific immune memory. The increased survival benefit of LTX-401-treated animals provides a rationale for further evaluation of the compound as an immunotherapeutic agent against solid malignancies. Citation Format: Brynjar Mauseth, Liv-Marie Eike, Ji-Hua Shi, Ketil Camilio, Heng Zhou, Allan Sauvat, Lígia C Gomes-da-Silva, Sylvèr Durand, Sabrina Forveille, Kristina Iribarren, Takahiro Yamazaki, Sylvie Souquere, Lucillia Bezu, Kevin Müller, Marion Leduc, Peng Liu, Liwei Zhao, Aurélien Marabelle, Laurence Zitvogel, Oliver Kepp, Guido Kroemer, Øystein Rekdal, Pål-Dag Line, Baldur Sveinbjørnsson. Induction of immunogenic cell death and tumor regression in murine animal models by a novel cytolytic compound, LTX-401 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5128. doi:10.1158/1538-7445.AM2017-5128