SMAC mimetics in action in chronic myeloid leukemia

In this issue of Blood, Nygrén and colleagues report the identification of apoptosis antagonists small mitochondrial activator of caspases (SMAC) mimetic compounds with the ability to stimulate natural killer (NK)-cell cytotoxicity in chronic myeloid leukemia (CML) cells.¹ This work suggests that the use of these compounds along with tyrosine kinase inhibitors (TKIs) could be a novel way of treating CML blast crisis or sensitizing CML cells to the effects of TKIs by stimulating in vivo NK-cell toxicity.

CML is the prototype of clonal hematopoietic stem-cell malignancy in which targeted therapies have shown a major and unprecedented success in the field of malignant hematology.² The use of TKIs in CML therapy has profoundly modified the natural history of the disease and prolonged survival.² Data from registries have also shown that in patients responding to TKI therapies, the survival of patients on treatment is similar to that of normal controls of the same age and sex.³ However, since the introduction of the first TKI imatinib almost 20 years ago, the need for other TKI inhibitors soon became evident due to the appearance of ABL-kinase mutations rendering leukemic cells resistant to therapies.² In addition, it became clear that the most primitive leukemic stem cells (LSCs) are resistant to all TKIs.^4,5 These findings explain the rapid molecular relapses in the majority of patients observed in TKI cessation trials.⁶ The LSC persistence also likely explains the progression of patients toward more the aggressive blast phase of CML, which has a dismal prognosis without allogeneic stem-cell transplantation.² Interestingly, in all TKI cessation trials, the most consistent finding in the characteristics of the patients who do not relapse was the detection of functional NK cells, which seemed to be correlated with the protection from relapse.⁷ NK cells have also been shown to be highly efficient against BCR-ABL-expressing cells with this sensitivity correlating with high expression of BCR-ABL.⁸ Given this background, NK cell-mediated cell therapies could represent a highly useful tool in patients in the blast phase of their disease in which the expression of BCR-ABL is increased compared with chronic phase CML. Likewise, would an in vivo NK-cell activation strategy help in the identification of compounds that could be used in CML, either to prevent progression or to treat blast phase using an “in vivo immunotherapy” strategy?

Nygrén et al used an original high-throughput drug screen assay with BCR-ABL expressing K562 blast crisis cell line as cell target to determine the drugs or compounds able to increase the NK cytotoxicity against leukemic cells expressing BCR-ABL. The experimental design consisted of the use of a coculture of NK cells along with K562 cells expressing a fluorochrome and a library of drugs that could either activate or inhibit a cytotoxic response. Luciferase readout served to evaluate the drugs that induced or inhibited the cytotoxicity. Using this protocol, the authors tested >500 small compounds. The compounds that they have identified have then been validated in independent assays using either K562 or primary CML cells. The most interesting of these belonged to the class of drugs that sensitize tumor cells to apoptosis designed as SMAC mimetics. These compounds mimic the effect of SMACs released from mitochondria and able to bind to the family of proteins named inhibitors of apoptosis (IAPs). This interactive binding inhibits the antiapoptotic activity of IAPs, leading to the sensitization of cancer cells to apoptosis.⁹ 

In single-cell transcriptome analyses, Nygrén et al also showed the induction of NK-cell activation markers. Cytotoxicity-inhibiting drugs reduced the NK-cell activation, and surprisingly, dasatinib had also a negative effect of NK-cell activation. In coculture experiments, the authors identified 2 compounds stimulating NK-cell activity against CML targets birinapant and LCL-161. They have shown that these compounds lead to the activation of nuclear factor κB targets in NK cells, therefore enhancing the cytotoxicity of NK cells. Finally, using CD34⁺ CML cells as well as blast crisis cells from a patient with CML, they have shown the induction of the enhancement of NK-cell cytotoxicity in the presence of SMAC mimetics.

Birinapant is an apoptosis antagonist that has been used in association with conventional therapies in clinical trials with an acceptable toxicity profile.¹⁰ The findings of Nygrén and colleagues suggest strongly that these compounds could be of clinical use in CML if these results can be confirmed in a larger series of patients with CML. Further studies are also needed to determine if these compounds should be added to NK-cell cultures in the context of an adoptive-cell therapy or to be administered directly to the patients as an intravenous infusion. In addition, the major problem of the LSC persistence in CML has not been addressed in this study. Nevertheless, the concept of enhancing NK-cell toxicity ex vivo or in vivo in CML by putting SMAC mimetic in action is highly interesting and requires further experimental development.

Conflict-of-interest disclosure: A.G.T. declares no competing financial interests.