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

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.

KEYWORDS:

• Chimeric antigen receptor
• mesothelin
• metabolism
• T cell receptor
• T cell Receptor Fusion Construct (TRuC®) T cells

Acknowledgments

Medical writing support, under the direction of the authors, was provided by Samuel Rochette, CMC Connect, a division of IPG Health Medical Communications, and funded by TCR² Therapeutics, in accordance with Good Publication Practice (GPP 2022) guidelines.⁴¹ The authors thank the following individuals for their contributions: Mike Lofgren, and Lipi Mukherjee for MH1 binder characterization; Philippe Kieffer-Kwon and Tiffany Chan for plasmid design and molecular biology support; Jason Rodriguez, Chris Rold, and Ahmar Aziz for lentivirus production support; Seema Shah for in vivo study support.

Disclosure statement

RT is a current employee and shareholder of TCR² Therapeutics. JD, BS, JG, HH, GG, RH, and SG are former employees and shareholders of TCR² Therapeutics. PAB is the scientific co-founder and shareholder of TCR² Therapeutics. No potential conflicts of interest were disclosed by GD and AM.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2182058

Additional information

Funding

This work was supported by TCR² Therapeutics.