Mesothelin-targeting T cells bearing a novel T cell receptor fusion construct (TRuC) exhibit potent antitumor efficacy against solid tumors. (31st December 2023)

• Record Type: Journal Article
• Authors: Ding, Jian; Guyette, Sarah; Schrand, Brett; Geirut, Jessica; Horton, Holly; Guo, Guangwu; Delgoffe, Greg; Menk, Ashley; Baeuerle, Patrick A.; Hofmeister, Robert; Tighe, Robert
• Is Part Of: Oncoimmunology. Volume 12:Number 1(2023)
• Publication Date: 2023-12-31
• Subjects: Chimeric antigen receptor -- mesothelin -- metabolism -- T cell receptor -- T cell Receptor Fusion Construct (TRuC®) T cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2023.2182058
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: T cell Receptor (TCR) Fusion Construct (TRuC®) T cells harness all signaling subunits of the TCR to activate T cells and eliminate tumor cells, with minimal release of cytokines. While adoptive cell therapy with chimeric antigen receptor (CAR)-T cells has shown unprecedented clinical efficacy against B-cell malignancies, monotherapy with CAR-T cells has suboptimal clinical efficacy against solid tumors, probably because of the artificial signaling properties of the CAR. TRuC-T cells may address the suboptimal efficacy of existing CAR-T therapies for solid tumors. Here, we report that mesothelin (MSLN)-specific TRuC-T cells (referred to as TC-210 T cells) potently kill MSLN+ tumor cells in vitro and efficiently eradicate MSLN+ mesothelioma, lung, and ovarian cancers in xenograft mouse tumor models. When benchmarked against MSLN-targeted BBζ CAR-T cells (MSLN-BBζ CAR-T cells), TC-210 T cells show an overall comparable level of efficacy; however, TC-210 T cells consistently show faster tumor rejection kinetics that are associated with earlier intratumoral accumulation and earlier signs of activation. Furthermore, in vitro and ex vivo metabolic profiling suggests TC-210 T cells have lower glycolytic activity and higher mitochondrial metabolism than MSLN-BBζ CAR-T cells. These data highlight TC-210 T cells as a promising cell therapy for treating MSLN-expressing cancers. The differentiated profile from CAR-T cells may translate into better efficacy and safety of TRuC-T cells for solid tumors.