Selective Inhibition of Interleukin-2 Inducible T Cell Kinase (ITK) Enhances Anti-Tumor Immunity in Association with Th1-skewing, Cytotoxic T cell Activation, and Reduced T Cell Exhaustion

ABSTRACT ITK is a tyrosine kinase expressed predominantly by T lymphocytes. In mice, selective knock-out of the ITK gene produces Th1 skewing of T helper cell differentiation. We synthesized a covalent ITK inhibitor, soquelitinib, that binds ITK with greater than 100-fold selectivity compared to binding to resting lymphocyte kinase (RLK). In vitro studies with normal or malignant T cells demonstrated that soquelitinib suppresses Th2 cytokine production preferentially with relative sparing of Th1 cytokines. Soquelitinib inhibits the in vivo growth of several syngeneic murine tumors including those that do not express ITK. Treatment with soquelitinib leads to increased tumor infiltration of normal CD8+ cells that possess enhanced T effector function. Soquelitinib inhibited expression of T cell exhaustion markers and was able to restore T effector function to exhausted cells. Pharmacologic selective ITK inhibition may represent a novel approach to cancer immunotherapy.