Intratumoral administration of unconjugated Accum™ impairs the growth of pre-established solid lymphoma tumors.

Autor: Bikorimana JP; Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, Quebec, Canada., El-Hachem N; Pediatric Hematology-Oncology Division, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Montreal, Quebec, Canada., Moreau M; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada., Lawson C; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada., Tai LH; Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada., Gonçalves M; Department of Molecular Biology, Université de Montréal, Montréal, Quebec, Canada., Abusarah J; Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada., Beaudoin S; Research and Development unit, Defence Therapeutics Inc., Montreal, Quebec, Canada., Stanga D; Research and Development unit, Defence Therapeutics Inc., Montreal, Quebec, Canada., Plouffe S; Research and Development unit, Defence Therapeutics Inc., Montreal, Quebec, Canada., Rafei M; Department of Microbiology, Infectious Diseases and Immunology, Université de Montréal, Montréal, Quebec, Canada.; Department of Molecular Biology, Université de Montréal, Montréal, Quebec, Canada.; Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2023 Dec; Vol. 114 (12), pp. 4499-4510. Date of Electronic Publication: 2023 Sep 29.
DOI: 10.1111/cas.15985
Abstrakt: The Accum™ technology was initially designed to enhance the bioaccumulation of a given molecule in target cells. It does so by triggering endosomal membrane damages allowing endocytosed products to enter the cytosol, escaping the harsh environmental cues of the endosomal lumen. In an attempt to minimize manufacturing hurdles associated with Accum™ conjugation, we tested whether free Accum™ admixed with antigens could lead to outcomes similar to those obtained with conjugated products. Surprisingly, unconjugated Accum™ was found to promote cell death in vitro, an observation further confirmed on various murine tumor cell lines (EL4, CT-26, B16, and 4 T1). At the molecular level, unconjugated Accum™ triggers the production of reactive oxygen species and elicits immunogenic cell death while retaining its innate ability to cause endosomal damages. When administered as a monotherapy to animals with pre-established EL4 T-cell lymphoma, Accum™ controlled tumor growth in a dose-dependent manner, and its therapeutic effect relies on CD4 and CD8 T cells. Although unconjugated Accum™ synergizes with various immune checkpoint inhibitors (anti-CTLA4, anti-PD-1, or anti-CD47) at controlling tumor growth, its therapeutic potency could not be further enhanced when combined with all three tested immune checkpoint inhibitors at once due to its dependency on a specific dosing regimen. In sum, we report in this study an unprecedented new function for unconjugated Accum™ as a novel anticancer molecule. These results could pave the path for a new line of investigation aimed at exploring the pro-killing properties of additional Accum™ variants as a mean to develop second-generation anticancer therapeutics.
(© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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