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Local delivery of accutox® synergises with immune-checkpoint inhibitors at disrupting tumor growth.
- Source :
- Journal of Translational Medicine; 6/3/2024, Vol. 22 Issue 1, p1-16, 16p
- Publication Year :
- 2024
-
Abstract
- Background: The Accum<superscript>®</superscript> platform was initially designed to accumulate biomedicines in target cells by inducing endosomal-to-cytosol escape. Interestingly however, the use of unconjugated Accum<superscript>®</superscript> was observed to trigger cell death in a variety of cancer cell lines; a property further exploited in the development of Accum<superscript>®</superscript>-based anti-cancer therapies. Despite the impressive pro-killing abilities of the parent molecule, some cancer cell lines exhibited resistance. This prompted us to test additional Accum<superscript>®</superscript> variants, which led to the identification of the AccuTOX<superscript>®</superscript> molecule. Methods: A series of flow-cytometry and cell-based assays were used to assess the pro-killing properties of AccuTOX<superscript>®</superscript> along with its ability to trigger the production of reactive oxygen species (ROS), endosomal breaks and antigen presentation. RNA-seq was also conducted to pinpoint the most prominent processes modulated by AccuTOX<superscript>®</superscript> treatment in EL4 T-cell lymphoma. Finally, the therapeutic potency of intratumorally-injected AccuTOX<superscript>®</superscript> was evaluated in three different murine solid tumor models (EL4, E0771 and B16) both as a monotherapy or in combination with three immune-checkpoint inhibitors (ICI). Results: In total, 7 Accum<superscript>®</superscript> variants were screened for their ability to induce complete cell death in 3 murine (EL4, B16 and E0771) and 3 human (MBA-MD-468, A549, and H460) cancer cell lines of different origins. The selected compound (hereafter refereed to as AccuTOX<superscript>®</superscript>) displayed an improved killing efficiency (~ 5.5 fold compared to the parental Accum<superscript>®</superscript>), while retaining its ability to trigger immunogenic cell death, ROS production, and endosomal breaks. Moreover, transcriptomic analysis revealed that low dose AccuTOX<superscript>®</superscript> enhances H2-K<superscript>b</superscript> cell surface expression as well as antigen presentation in cancer cells. The net outcome culminates in impaired T-cell lymphoma, breast cancer and melanoma growth in vivo especially when combined with anti-CD47, anti-CTLA-4 or anti-PD-1 depending on the animal model. Conclusions: AccuTOX<superscript>®</superscript> exhibits enhanced cancer killing properties, retains all the innate characteristics displayed by the parental Accum<superscript>®</superscript> molecule, and synergizes with various ICI in controlling tumor growth. These observations will certainly pave the path to continue the clinical development of this lead compound against multiple solid tumor indications. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14795876
- Volume :
- 22
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Journal of Translational Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 177647498
- Full Text :
- https://doi.org/10.1186/s12967-024-05340-2