Graduate Student Jesika DeDonato

"TGF-β Signaling Pathway Inhibition to Enhance CAR T Cell Antitumor Efficacy"

Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that involves genetically engineering T cells with CAR proteins as a method to kill cancerous cells. This treatment works effectively because CARs can recognize and bind to specific antigens, such as those residing on cancer cells. This enables CARs to recruit T cells from the immune system to the cancerous site, resulting in apoptosis. However, T cells may become incapable of killing certain cells due to a phenomenon called exhaustion1. Recent research has focused on trying to combat T cell exhaustion to improve the efficacy of this immunotherapy.

Tang et al. have investigated the signaling blockade of the cytokine called transforming growth factor β (TGF-β) which suppresses T cell activation in the tumor microenvironment. CAR T cells were edited to knockout TGF-β receptor II and tumor elimination efficacy was observed in both in vitro and in vivo models. CAR T cell survival and proliferation were increased in all models, demonstrating the rescue from the negative effects of TGF-β2.

Chen et al. explored the co-targeting of TGF-β and the immune checkpoint called cell death protein 1 (PD-1) by trap proteins. The trap proteins contain an anti-PD-1 single-chain fragment variable fused with a TGF-β receptor II ectodomain. Studies focused on the observation of antitumor efficacy in both in vitro and in vivo models. These models demonstrated that CAR T cells with trap protein exhibit improved proliferation and tumor progression inhibition3.

(1) Alnefaie, A.; et al. Chimeric Antigen Receptor T-Cells: An Overview of Concepts, Applications, Limitations, and Proposed Solutions. Front. Bioeng. Biotechnol. 2022, 10, 797440. https://doi.org/10.3389/fbioe.2022.797440.

(2) Tang, N.; et al. TGF-β Inhibition via CRISPR Promotes the Long-Term Efficacy of CAR T Cells against Solid Tumors. JCI Insight 2020, 5 (4), e133977. https://doi.org/10.1172/jci.insight.133977.

(3) Chen, X.; et al. Secretion of Bispecific Protein of Anti-PD-1 Fused with TGF-β Trap Enhances Antitumor Efficacy of CAR-T Cell Therapy. Molecular Therapy - Oncolytics 2021, 21, 144–157. https://doi.org/10.1016/j.omto.2021.03.014.