Comments for:
Abstract
BACKGROUND. Ibrutinib has been shown to have immunomodulatory effects by inhibiting Bruton’s tyrosine kinase (BTK) and IL-2–inducible T cell kinase (ITK). The relative importance of inhibiting these 2 kinases has not been examined despite its relevance to immune-based therapies. METHODS. Peripheral blood mononuclear cells from chronic lymphocytic leukemia (CLL) patients on clinical trials of ibrutinib (BTK/ITK inhibitor; n = 19) or acalabrutinib (selective BTK inhibitor; n = 13) were collected serially. T cell phenotype, immune function, and CLL cell immunosuppressive capacity were evaluated. RESULTS. Ibrutinib markedly increased CD4+ and CD8+ T cell numbers in CLL patients. This effect was more prominent in effector/effector memory subsets and was not observed with acalabrutinib. Ex vivo studies demonstrated that this may be due to diminished activation-induced cell death through ITK inhibition. PD-1 and CTLA-4 expression was significantly markedly reduced in T cells by both agents. While the number of Treg cells remained unchanged, the ratio of these to conventional CD4+ T cells was reduced with ibrutinib, but not acalabrutinib. Both agents reduced expression of the immunosuppressive molecules CD200 and BTLA as well as IL-10 production by CLL cells. CONCLUSIONS. Ibrutinib treatment increased the in vivo persistence of activated T cells, decreased the Treg/CD4+ T cell ratio, and diminished the immune-suppressive properties of CLL cells through BTK-dependent and -independent mechanisms. These features provide a strong rationale for combination immunotherapy approaches with ibrutinib in CLL and other cancers. TRIAL REGISTRATION. ClinicalTrials.gov NCT01589302 and NCT02029443. Samples described here were collected per OSU-0025. FUNDING. The National Cancer Institute.
Authors
Meixiao Long, Kyle Beckwith, Priscilla Do, Bethany L. Mundy, Amber Gordon, Amy M. Lehman, Kami J. Maddocks, Carolyn Cheney, Jeffrey A. Jones, Joseph M. Flynn, Leslie A. Andritsos, Farrukh Awan, Joseph A. Fraietta, Carl H. June, Marcela V. Maus, Jennifer A. Woyach, Michael A. Caligiuri, Amy J. Johnson, Natarajan Muthusamy, John C. Byrd
Ibrutinib therapy in chronic lymphocytic leukemia (CLL): effects on the T cell compartment
Submitter: Jan A. Burger | jaburger@mdanderson.org
Authors: Ekaterina Kim and Jan A. Burger
The University of Texas MD Anderson Cancer Center
Published October 17, 2017
We read with interest the publication by Long (1) describing that treatment with the BTK inhibitor ibrutinib increases CD4 and CD8 T cell numbers in CLL patients. As potential mechanism, the authors discuss diminished activation-induced T cell death (AICD) due to ITK inhibition. These findings are in contrast with three other studies, which reported a decline and normalization of elevated T cell numbers in CLL patients undergoing ibrutinib therapy (2-4), along with normalization of elevated Th1, Th2, and Th17 cytokine levels (4). These discrepancies make this subject worth further discussing.
In untreated CLL patients, PB T cell numbers are elevated and oligoclonal (4-8). This is, at least in part, due to CLL antigen-driven expansion of T cells that can support CLL cell proliferation in “proliferation centers” of secondary lymphatic tissues (9), resembling T cell help during expansion of normal B cell as part of adaptive immune responses. CLL-T cell cross talk is a consequence of CLL cell activation via the B cell receptor (BCR) pathway, which promotes engagement between CLL and T cells via secretion of chemokines (i.e. CCL3, CCL4) (10, 11), utilizing again mechanism of normal adaptive immune responses (12). Once BCR signaling is disrupted by ibrutinib, CLL-T cell interactions are rapidly dissolved, while the infiltrated enlarged lymphatic tissues in CLL patients rapidly shrink. High plasma levels of BCR-related chemokines CCL3 and CCL4 rapidly decrease and normalize within days on therapy (3, 13). Consequently, CLL-driven T cell clones, after disengagement with counterpart CLL cells, are prone to undergo deprivation-induced apoptosis. This type of T cell death termed activated cell-autonomous death (ACAD) is distinct from AICD, which requires T cell receptor re-stimulation (14). Elimination of oligoclonal T cells and diversification of the T cell repertoire, as seen in our series (4), favor the ACAD concept. While the data by Long are novel and provocative, we believe a larger body of clinical and pre-clinical evidence demonstrates reduction and normalization of the expanded T cell compartment during ibrutinib therapy, and suggests ACAD rather than inhibition of AICD as mechanism modulating the T cell compartment. Differences in patient populations likely explain some of the discrepancies. We noted rather low T cell numbers in pre-treatment samples from Long et al. (1), which could be due to recent treatment with nucleoside analogs. Hence, the complexity of patient populations and treatment effects can bias outcome and can lead, as in this case, to opposite findings and interpretation.
References
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