Profound inhibition of antigen-specific T-cell effector functions by dasatinib

Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of clasatinib on T-cell function. The effect of clasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator. Experimental Design: Purified human CD3(+) cells and virus-specific CD8(+) T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFN-gamma, and tumor necrosis factor alpha), clegranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction. Results: Both clasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and clegranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4(+) T cells seemed to be more sensitive to these effects than CD8+ T cells, and naive T cells more sensitive than memory T-cell subsets. The inhibitory effects of clasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations. Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of clasatinib as an immunosuppressant in the fields of transplantation and T-cell - driven autoimmune diseases.