Selective ITK Inhibition by CPI-818: Th1 Promotion and Tumor Response in Canine T Cell Lymphomas

The study introduces CPI-818, a newly discovered inhibitor targeting ITK, a protein that influences T cell receptor signaling pathways. Mice lacking ITK show impaired Th2 differentiation but maintain Th1 differentiation capabilities, suggesting the importance of selectively inhibiting ITK to control Th2 responses without compromising Th1 immunity. ITK is also prevalent in T cell cancers, and its activation can increase the expression of GATA-3, which is linked to poor survival rates. CPI-818 is shown to be an effective and selective inhibitor of ITK, with a significant preference over RLK and BTK.

The compound irreversibly binds to ITK, particularly at CYS-442, as confirmed by mass spectrometry. This binding leads to the inhibition of key signaling proteins in T cells and a reduction in IL2 secretion. CPI-818 also suppresses the proliferation of malignant T cells from patients with Sezary Syndrome. In animal models, treatment with CPI-818 resulted in an increased Th1 response, indicated by a higher IFNγ/IL-4 ratio.

Furthermore, in human PBMCs, CPI-818 significantly reduced IL-4 production, promoting a Th1 bias. The compound was also tested in dogs with T cell lymphomas, where it demonstrated full ITK occupancy and anti-tumor activity, with complete and partial responses observed. CPI-818 was well-tolerated, with no adverse effects on normal lymphocyte counts.

The findings support the potential of CPI-818 in treating T cell malignancies and warrant further clinical trials in humans. The study was presented at the American Association for Cancer Research Annual Meeting in 2019.