Antitumor Activity Of The Oncolytic Peptide Ltx-315 In Syngeneic Tumor Models

Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in a number of species as a defense mechanism for eukaryotic cells against pathogens and are an integral part of the innate immune system. CAPs have a broad spectrum of activities including antimicrobial and anticancer while being less cytotoxic toward non-malignant cells. The potential therapeutic application against cancer has spawned an interest in developing oncolytic agents that display a new mode of action to overcome the potential drug resistance associated with other current therapeutics. The anticancer effects of CAPs are still under investigation, but several peptides have already exhibited a promising potential with cytotoxic activities against a broad spectrum of tumor cells. Oncolytic peptides exert their activity through either a membranolytic mode of action or an interaction with intracellular targets, or a combination of both. LTX-315 (K-K-W-W-K-K-W-Dip-K-NH2), a novel oncolytic peptide developed by Lytix Biopharma AS has the potential to adopt an amphipathic helical coil structure. In vitro studies have demonstrated that it was highly effective against both drug-resistant and drug-sensitive cancer cells from several organ origins, with lower toxicity toward normal cells. LTX-315 was designed for intratumoral treatment of transdermal lesions. Previously, LTX-315 has been shown to induce complete regression of B16 melanomas and long lasting antitumor immune responses. Histological analyses of treated tumors revealed extensive hemorrhagic necrosis and infiltration of CD3+ T cells. Moreover, mRNA levels of inflammatory cytokines such as IL1β, IL6 and IL18 were found to be increased in the tumor tissue after LTX-315 treatment. The treatment did also prevent lung metastasis in mice re-challenged with B16F1 cells intravenously. Due to its oncolytic mode of action, LTX-315 induces immunogenic cell death through the release of danger-associated molecular pattern molecules and tumor antigens. Recently, we have demonstrated that when subcutaneously established EMT-6 tumors (inoculated into both flanks of the animal) were treated intratumorally with LTX-315, an antitumor response was observed with a T/C ratio of 17% 19 days post start of treatment. Furthermore, an abscopal effect of LTX-315 on the untreated tumor was also reported but only when it was combined with anti-PD-L1 antibody. At the end of study, 50% of mice that had received the combination therapy were still alive vs 30% and 40% in the groups treated with LTX-315 or anti-PD-L1 antibody alone, respectively. In conclusion, LTX-315 seems to be an ideal combinations partner for immune checkpoint inhibitors. Citation Format: Ketil Andre Camilio, Baldur Sveinbjornsson, Sylvie Maubant, Guillaume Serin, Jean-Francois Mirjolet, Francis Bichat, Oystein Rekdal. Antitumor activity of the oncolytic peptide LTX-315 in syngeneic tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 328.