Imatinib mesylate: a novel immune suppressive agent?

Comment on Dietz et al, page 1094

Imatinib mesylate, a small molecule inhibitor of the BCR-ABL, c-kit, and PDGF tyrosine kinases, also may inhibit T-cell–specific kinases, either directly or indirectly, which may contribute to the inhibition of selected T-cell functions.

Imatinib mesylate is an inhibitor of the protein tyrosine kinase domain associated with BCR-ABL, as well as those of the platelet-derived growth factor (PDGF) and C-kit receptors, but is not generally thought to inhibit other members of the type II receptor kinase family.^1,2  However, since tyrosine kinases catalyze the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues of substrate proteins, it is conceivable that other tyrosine kinases could be inhibited. Imatinib mesylate was originally selected as a compound to inhibit phosphate transfer at the ATP-binding site rather than as a selective BCR-ABL inhibitor. A compound that had these characteristics was identified and then was chemically altered to generate the molecule (STI571; imatinib mesylate) that has had a meteoric rise with its rapid FDA approval and worldwide use. The drug has excellent oral bioavailability and it was identified that doses as low as 300 mg daily can achieve an in vitro serum trough level of 1 μM/L, which corresponded to a threshold necessary to achieve therapeutic benefits of BCR-ABL inhibition. Clinical results that confirm that other tyrosine kinases have different sensitivities include the recent demonstration that in hypereosinophilic syndrome, inhibition of the PDGF-α receptor kinase activity could be achieved with oral delivery as low as 100 mg imatinib mesylate daily.³  Thus, it is not inconceivable that, given the many other tyrosine kinases present within the cell, some selective inhibition could be found due to potential “promiscuity” of the molecule.FIG1 

Dietz and colleagues demonstrate in their study, published in this issue of Blood, that physiologic functions of T cells can be inhibited by imatinib mesylate. In vitro stimulation and proliferation assays were inhibited. In addition, a reduction in delayed hypersensitivity was shown as an in vivo demonstration that imatinib mesylate could inhibit T-cell functions, albeit with fairly significant treatment doses. On further examination, the authors identified that presumed autophosphorylation of Lck and the downstream phosphorylation of extracellular signal-related kinase 1/2 could be inhibited in vitro. This report may represent a unique finding, with the expansion of the cellular kinase inhibition repertoire extended to Lck, or actually may represent a scenario in which multiple, as-yet undetected other cellular kinases might be inhibited by the drug. In clinical circumstances where a dominant response is pursued, such as in the eradication of the burden of chronic myelogenous leukemia, these other inhibitory events may not be discernible. However, as we maintain patients for years in the Philadelphia-negative state with imatinib mesylate, we may find that these other secondary kinase inhibitions become clinically relevant.

To date, in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors, we have not seen an excess of infections related to immune deficiency. Of interest, in a retrospective analysis, investigators at the M. D. Anderson Cancer Center had suggested that there are more frequent herpes zoster infections in patients treated with imatinib mesylate when compared with a similar cohort of CML patients previously treated with alpha interferon.⁴  Whether this is coincidental or represents a snapshot of immune deficits that will become clinically apparent in the future is unclear. Whether this drug will ever have a role as an immune suppressive agent in circumstances such as autoimmune disease, as the authors suggest, will require confirmation of these intriguing results; can be established only by careful preclinical and clinical studies; and must take into account ultimately the cost of the drug balanced with patients' need versus available alternative drugs.