mPH-804: Intratumoral TIGIT Inhibitor Driving Tumor Growth Suppression and Inflammatory Microenvironment Shift

The abstract discusses the potential of targeting TIGIT, a molecule involved in immune checkpoint pathways, to enhance cancer treatment. The INTASYL RNAi technology has been utilized to develop a compound, mPH-804, designed to silence TIGIT in immune cells. This technology is self-delivering and stable, allowing for efficient cellular uptake and in situ delivery.

In a cell-based screen, mPH-804 was identified as a potent compound that significantly reduced TIGIT mRNA and protein levels in a murine cell line. The compound was then tested in vivo using a CT-26 murine tumor model. Mice with implanted tumors were given intratumoral injections of mPH-804 at varying doses. The control groups received either a vehicle control (PBS), a non-targeting control RNAi (NTC), or an anti-TIGIT antibody.

The treatment with mPH-804 resulted in a dose-dependent reduction in tumor growth, with a significant decrease in tumor burden observed by day 11. Analysis of Tumor-Infiltrating Lymphocytes (TILs) showed a substantial knockdown of TIGIT and an increase in CD8+ T cells in the mPH-804 treated group. Additionally, there was an upregulation of T cell activation markers CD25 and CD69 in intratumoral T cells.

The study concludes that mPH-804 has the potential to suppress TIGIT in the tumor microenvironment, enhance the function of effector T cells, and inhibit tumor growth. The compound's ability to be efficiently delivered to immune cells within the tumor without special formulations suggests that local TIGIT silencing could be a promising therapeutic approach. Further investigation of this approach in cancer patients is warranted based on these findings.