Author: Eksteen, J Johannes ; Mælandsmo, Gunhild M ; Fleten, Karianne Giller ; Rekdal, Øystein ; Camilio, Ketil André ; Flatmark, Kjersti ; Mauseth, Brynjar ; Sveinbjørnsson, Baldur ; Vasskog, Terje

AbstractOncolytic peptides represent a novel, promising cancer treatment strategy with activity in a broad spectrum of cancer entities, including colorectal cancer (CRC). Cancer cells are killed by immunogenic cell death, causing long-lasting anticancer immune responses, a feature of particular interest in non-immunogenic CRC. Oncolytic peptides DTT-205 and DTT-304 were administered by intratumoral injection in subcutaneous tumors established from murine CRC cell lines CT26 and MC38, and complete regression was obtained in the majority of animals. When cured animals were rechallenged by splenic injection of tumor cells, 1/23 animals developed liver metastases, compared to 19/22 naïve animals. Treatment with both peptides was well tolerated, but monitoring post-injection hemodynamic parameters in rats, less extensive changes were observed with DTT-205 than DTT-304, favoring DTT-205 for future drug development. DTT-205 was subsequently shown to have strong in vitro activity in a panel of 33 cancer cell lines. In conclusion, both peptides exerted a strong inhibitory effect in two immunocompetent CRC models and induced a systemic effect preventing development of liver metastases upon splenic rechallenge. If a similar effect could be obtained in humans, these drugs would be of particular interest for combinatory treatment with immune checkpoint inhibitors in metastatic CRC.

Cell Death & DiseaseQ1 · BIOLOGY

Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals

Q1 · BIOLOGY

ArticleOA

Author: Leduc, Marion ; Zhao, Liwei ; Bezu, Lucillia ; Xie, Wei ; Kepp, Oliver ; Liu, Peng ; Eksteen, J Johannes ; Forveille, Sabrina ; Sveinbjørnsson, Baldur ; Kroemer, Guido ; Mondragón, Laura ; Zhou, Heng ; Sauvat, Allan ; Gomes-da-Silva, Lígia C ; Mauseth, Brynjar ; Rekdal, Øystein ; Souquere, Sylvie ; Iribarren, Kristina ; Zitvogel, Laurence

AbstractOncolytic peptides and peptidomimetics are being optimized for the treatment of cancer by selecting agents with high cytotoxic potential to kill a maximum of tumor cells as well as the capacity to trigger anticancer immune responses and hence to achieve long-term effects beyond therapeutic discontinuation. Here, we report on the characterization of two novel oncolytic peptides, DTT-205 and DTT-304 that both selectively enrich in the lysosomal compartment of cancer cells yet differ to some extent in their cytotoxic mode of action. While DTT-304 can trigger the aggregation of RIP3 in ripoptosomes, coupled to the phosphorylation of MLKL by RIP3, DTT-205 fails to activate RIP3. Accordingly, knockout of either RIP3 or MLKL caused partial resistance against cell killing by DTT-304 but not DTT-205. In contrast, both agents shared common features in other aspects of pro-death signaling in the sense that their cytotoxic effects were strongly inhibited by both serum and antioxidants, partially reduced by lysosomal inhibition with bafilomycin A1 or double knockout of Bax and Bak, yet totally refractory to caspase inhibition. Both DTT-304 and DTT-205 caused the exposure of calreticulin at the cell surface, as well as the release of HMGB1 from the cells. Mice bearing established subcutaneous cancers could be cured by local injection of DTT-205 or DTT-304, and this effect depended on T lymphocytes, as it led to the establishment of a long-term memory response against tumor-associated antigens. Thus, mice that had been cured from cancer by the administration of DTT compounds were refractory against rechallenge with the same cancer type several months after the disappearance of the primary lesion. In summary, DTT-205 and DTT-304 both have the capacity to induce immunotherapeutic oncolysis.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Preclinical	NO	Oslo universitetssykehus HF	-
Colorectal Cancer	Preclinical	NO	Lytix Biopharma AS	-

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