Exploring TT-702: A Promising A2B Receptor Antagonist in Cancer Therapy

The abstract discusses the role of adenosine signaling through A2A and A2B receptors in immune regulation. A2AR has a strong affinity for adenosine, while A2BR is less sensitive and is activated under certain conditions when adenosine levels are high. Tumors often have high adenosine levels and hypoxia, which can increase A2BR expression on cancer and immune cells. TT-702 is a new, selective, and potent A2BR antagonist that can be taken orally. It was found to slow tumor growth by improving the function of dendritic cells and T-cells, reducing myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs), and inhibiting cancer cell growth, fibrosis, and the formation of new blood vessels.

The effectiveness of TT-702 was tested through various assays, including its impact on cAMP production and its ability to counteract immune suppression caused by NECA. The drug was also evaluated in mouse models of melanoma and colorectal cancer, where it was administered at different doses alongside other treatments like anti-PD-1 and enzalutamide. TT-702 showed high binding affinity to human A2BR and was significantly more selective for this receptor compared to others.

In combination with enzalutamide, TT-702 demonstrated enhanced inhibitory effects on prostate cancer cell growth. It also prevented the suppression of dendritic cell differentiation and T cell activation caused by NECA, whereas an A2AR antagonist did not affect these processes. TT-702 increased the number of immune-stimulatory cells and decreased immunosuppressive cells in tumors, and it reduced tumor growth in a dose-dependent manner.

The combination of TT-702 with anti-PD-1 was particularly effective in inhibiting tumor growth in mice. The drug also reduced fibrosis and angiogenesis in tumors, which could improve the tumor microenvironment for T cell infiltration and cancer elimination. TT-702 is a promising new drug with potential for treating various types of difficult-to-treat and aggressive tumors, either alone or in combination with other therapies. It has shown good safety and pharmacokinetic profiles in animal studies and is expected to move into clinical development in 2021.