Two targets for the price of one

In this issue of Blood, Dubovsky et al show that ibrutinib inhibits interleukin-2 (IL-2) inducible kinase (ITK) and thereby modulates T-cell signaling and function.¹ 

Ibrutinib is an effective inhibitor of the B-cell receptor (BCR) signaling pathway and has demonstrated clinical efficacy in the treatment of various B-cell malignancies. Data reported by Dubovsky et al¹  show that ibrutinib also inhibits IL-2 ITK and thereby modulates T-cell signaling and function.

Many B-cell malignancies, particularly chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and activated B cell–type diffuse large B-cell lymphoma, have constitutive activation of the BCR signaling pathway and are particularly susceptible to inhibition of this pathway.^2,3  Bruton’s tyrosine kinase (BTK) is a mediator of the BCR signaling pathway and has been implicated in the pathogenesis of B-cell malignancies. Ibrutinib, a BTK inhibitor, has been used to treat various B-cell malignancies and has shown particularly significant activity in treating patients with relapsed or refractory mantle cell lymphoma, relapsed or refractory CLL, or activated B cell–type diffuse large B-cell lymphoma.^4,5  The agent also has significant promise in Waldenstrom macroglobulinemia.

Although ibrutinib has been found to be a potent inhibitor of BTK and downstream signaling of the BCR pathway, data have also been generated that suggest that ibrutinib can inhibit other important pathways. Studies have shown that ibrutinib is able to inhibit activation and function of human basophils. BTK is also able to inhibit the secretion of tumor necrosis factor-α, IL-1β, and IL-6 from primary monocytes, particularly those present in autoimmune arthritis.⁶  Furthermore, BTK inhibition inhibits the release of histamine, tumor necrosis factor-α, IL-8, and monocyte chemoattractant protein-1 from activated human mast cells. In B-cell malignancies such as multiple myeloma, BTK inhibition also inhibits multiple cytokines and chemokines secreted by autoclasts and bone marrow stromal cells. Furthermore, BTK inhibition with ibrutinib also decreased stromal cell-derived factor-1–induced migration of multiple myeloma cells and down-regulated macrophage-inflammatory protein-1α in multiple myeloma cells.⁷ 

The data presented by Dubovsky et al¹  show that ibrutinib specifically inhibits the differentiation and activation of T helper 2 (Th2) T cells and skews development in favor of Th1-based immune responses. This bias toward Th1 cells promotes a more effective antitumor immune response, thereby improving the outcome of patients with CLL and other B-cell malignancies. The authors also show that ITK inhibition has a similar effect in responses to various pathogens and that ibrutinib plays an important role in infectious disease models.

Chronic inflammation and proinflammatory processes have been known to play a role in malignancy in general. Production of cytokines, including IL-1 and IL-6, is considered likely to aid in the development or promotion of tumors. In contrast, successful cancer immune surveillance is mediated by tumor-specific CD4+ T cells and is associated with proinflammatory cytokines, particularly cytokines that promote a Th1 phenotype.⁸  However, the balance between Th1 and Th2 T cells within malignancies is commonly disturbed. Studies in B-cell malignancies have suggested dysregulation of the Th1/Th2 cytokine ratios, with a preponderance of Th2 cytokines secreted rather than cytokines that promote a Th1 response.⁹  This results in a compromised ability of the immune system to irradiate the malignant clone. Studies in B-cell CLL have shown that the cytokine profile shifts toward a Th2 type as the disease progresses. Furthermore, B cells chronically helped by idiotype-specific Th2 cells have been shown to develop into large B-cell lymphomas with significant cytogenetic aberrations. This appears to be due to bidirectional collaboration with the Th2 cells. The previously mentioned results all suggest that the Th2 phenotype inhibits an effective antitumor immune response and may promote and even induce B-cell malignancies.¹⁰ 

As shown in the article by Dubovsky et al,¹  the small molecule ibrutinib, which inhibits BTK signaling and suppresses malignant B-cell growth, also inhibits ITK and thereby skews the development of T cells toward a Th1 phenotype. The authors show in neoplastic mouse models, including a mouse model of CLL and parasitic infection models using Leishmania major and infectious disease models using Listeria monocytogenes, that ibrutinib is able to specifically promote Th1 responses, resulting in improved outcomes. These findings strongly suggest a pleiotropic mechanism of action of ibrutinib. Not only is there a specific inhibition and downregulation of BCR signaling directly inhibiting the proliferation and survival of the malignant B cell, there is also inhibition of ITK with a dramatic change in the tumor microenvironment promoting a Th1 response that promotes immune regulation that inhibits malignant cell growth (see figure). The findings of this study suggest that ibrutinib may be successful in the treatment of a variety of diseases, particularly B-cell malignancies, because of its effect not only on the malignant B cell and on the immune response and tumor microenvironment.