Deciphering the Immune-Boosting Potential of CB-708: A CD73 Inhibitor for Cancer Therapy

The study explores the role of adenosine (ADO) in the tumor microenvironment and its impact on immune response, where high levels of ADO are known to suppress the immune system. The production of extracellular ADO is linked to the enzymes CD39 and CD73, which convert ATP to ADO. A new compound, CB-708, has been developed to inhibit CD73 and is being tested for its potential as a cancer treatment.

The compound's efficacy was tested in vitro using a malachite green assay on recombinant CD73 and cells expressing CD73. It was also evaluated for its selectivity against similar enzymes. The compound's ability to inhibit CD73 in plasma was measured using liquid chromatography/mass spectrometry (LC/MS), and its impact on human CD8+ T cells was assessed through cytokine production and cell proliferation assays. The EG7 tumor model in mice was utilized to evaluate the therapeutic effects of CB-708.

Results showed that CB-708 is a potent inhibitor of both soluble and cell-bound human CD73 with high selectivity, as it does not inhibit other related enzymes. The compound was effective in reversing the suppressive effects of AMP on human CD8+ T cells and demonstrated significant tumor growth inhibition in the EG7 mouse model. Furthermore, combining CB-708 with anti-PD-L1 therapy enhanced the tumor growth inhibition.

In conclusion, CB-708 is a highly potent and orally bioavailable inhibitor of CD73 that can reverse the immunosuppressive effects of ADO both in vitro and in vivo, leading to anti-tumor activity. The compound is anticipated to enter clinical development in 2019. The study was presented at the American Association for Cancer Research Annual Meeting in Atlanta, GA, in March-April 2019.