Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

Dubovsky, Jason A.; Beckwith, Kyle A.; Natarajan, Gayathri; Woyach, Jennifer A.; Jaglowski, Samantha; Zhong, Yun‐Shi; Hessler, Joshua; Liu, Ta-Ming; Chang, Betty; Larkin, Karilyn; Stefanovski, Matthew; Chappell, Danielle L.; Frissora, Frank; Smith, Lisa L.; Smucker, Kelly A.; Flynn, Joseph M.; Jones, Jeffrey A.; Andritsos, Leslie A.; Maddocks, Kami J.; Lehman, Amy; Furman, Richard R.; Sharman, Jeff P.; Mishra, Anjali; Caligiuri, Michael A.; Satoskar, Abhay R.; Buggy, Joseph J.; Muthusamy, Natarajan; Johnson, Amy J.; Byrd, John C.

doi:10.1182/blood-2013-06-507947

Cited by 688 publications

(681 citation statements)

References 43 publications

(50 reference statements)

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“…Moreover, in longitudinal analyses of patients on ibrutinib we did not detect a Th1 shift in the CD4 subsets and the cytokine profile in contrast to what had been reported from pre-clinical studies. 10 A variety of reasons may account for this discrepancy: (i) our patient number was far too low to detect subtle differences; (ii) the Th1 shift was observed ex vivo in CD4 cells from healthy individuals and CLL patients and was confirmed in a pre-clinical mouse model. In vivo analyses of blood from patients following alloSCT may yield different findings; (iii) in the previous study, serum cytokine levels were regarded as surrogate markers for a Th1 shift.…”

Section: Discussionmentioning

confidence: 99%

“…The immunosuppressive effect was exclusively found in CD4 Th2 cells, because activation of this T-cell subset is dependent on ITK. 10 Th1 cells are mainly involved in cell-mediated immunity by activating macrophages, natural killer cells and CD8 + T cells, and have been associated with the initiation of acute GvHD. 11 On the other hand, Th2 cells are considered to be responsible for the development of chronic GvHD.…”

Section: Introductionmentioning

confidence: 99%

“…[12][13][14] In vitro assays using blood from patients with CLL and a pre-clinical mouse model demonstrated a shift from Th2 toward Th1 dominated CD4 immunity upon exposure to ibrutinib. 10 This report prompted us to establish immune-monitoring for patients who received ibrutinib after alloSCT. The idea was to withhold ibrutinib in case of a shift of CD4 immunity toward Th1 as a danger signal, which could indicate imminent activation of GvHD.…”

Section: Introductionmentioning

confidence: 99%

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Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

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Teipel

Heidenreich

et al. 2016

Bone Marrow Transplant

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Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cellmediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Link

Teipel

Heidenreich

et al. 2016

Bone Marrow Transplant

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“…The pros and cons of continuing BCRi post alloSCT are also unknown as there are concerns for a possible higher incidence of GvHD under either idelalisib or ibrutinib because of inhibition of regulatory T-cell function 48 and increased Th1 T-cell activity, 49 respectively.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of cisplatin-based immunochemotherapy plus alloSCT in high-risk chronic lymphocytic leukemia: final results of a prospective multicenter phase 2 HOVON study

Gelder

Oers

Alemayehu³

et al. 2016

Bone Marrow Transplant

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Allogeneic stem cell transplantation (alloSCT) remains the only curative option for CLL patients. Whereas active disease at the time of alloSCT predicts poor outcome, no standard remission-induction regimen exists. We prospectively assessed outcome after cisplatin-containing immune-chemotherapy (R-DHAP) followed by alloSCT in 46 patients (median age 58 years) fulfilling modified European Society for Blood and Marrow Transplantation (EBMT) CLL Transplant Consensus criteria being refractory to or relapsed (R/R) o1 year after fludarabine or o 2 years after fludarabine-based immunochemotherapy or R/R with del(17p). Twenty-nine patients received ⩾ 3 cycles of R-DHAP and sixteen o 3 cycles (4 because of disease progression, 8 for toxicity and 4 toxic deaths). Overall rate of response to R-DHAP was 58%, 31 (67%) proceeded to alloSCT after conditioning with fludarabine and 2 Gy TBI. Twenty (65%) remained free from progression at 2 years after alloSCT, including 17 without minimal residual disease. Intention-totreat 2-year PFS and overall survival of the 46 patients were 42 and 51% (35.5 months median follow-up); del(17p) or fludarabine refractoriness had no impact. R-DHAP followed by alloSCT is a reasonable treatment to be considered for high-risk CLL patients without access or resistance to targeted therapies.

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“…One recent member of this class is ibrutinib, a covalent inhibitor of BTK (Bruton's tyrosine kinase) (16), a key enzyme in the B-cell receptor signaling pathway and a very effective therapy for chronic lymphocytic leukemia (CLL) Mantle cell lymphoma (MCL) and Waldenstrom's Macroglobulinemia (17,18). This drug also inhibits other tyrosine kinases (16), including ITK (interleukin-2-inducible T-cell kinase), an enzyme important for the survival of Th2 T cells (19), and therefore ibrutinib might have immunomodulatory effects in addition to direct anti-lymphoma effects.…”

mentioning

confidence: 99%

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

Sagiv-Barfi

Kohrt

Czerwinski

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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381

323

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Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.ibrutinib | PD-1/PD-L1 blockade | lymphoma | solid tumors

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Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes

Abstract: Key Points Ibrutinib is the first clinically viable irreversible ITK inhibitor. Ibrutinib inhibits the formation of Th2 but not Th1 immunity.

Cited by 688 publications

References 43 publications

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation

Efficacy of cisplatin-based immunochemotherapy plus alloSCT in high-risk chronic lymphocytic leukemia: final results of a prospective multicenter phase 2 HOVON study

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK

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