11 results on '"Maddocks K"'
Search Results
2. The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation.
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Reiff SD, Mantel R, Smith LL, Greene JT, Muhowski EM, Fabian CA, Goettl VM, Tran M, Harrington BK, Rogers KA, Awan FT, Maddocks K, Andritsos L, Lehman AM, Sampath D, Lapalombella R, Eathiraj S, Abbadessa G, Schwartz B, Johnson AJ, Byrd JC, and Woyach JA
- Subjects
- Adenine analogs & derivatives, Animals, Disease Models, Animal, Humans, Mice, Piperidines, Protein Kinase Inhibitors pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Targeted inhibition of Bruton tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has improved outcomes for patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here, we describe preclinical investigations of ARQ 531, a potent, reversible inhibitor of BTK with additional activity against Src family kinases and kinases related to ERK signaling. We hypothesized that targeting additional kinases would improve global inhibition of signaling pathways, producing more robust responses. In vitro treatment of patient CLL cells with ARQ 531 decreases BTK-mediated functions including B-cell receptor (BCR) signaling, viability, migration, CD40 and CD86 expression, and NF-κB gene transcription. In vivo , ARQ 531 was found to increase survival over ibrutinib in a murine Eμ-TCL1 engraftment model of CLL and a murine Eμ-MYC/TCL1 engraftment model resembling Richter transformation. Additionally, ARQ 531 inhibits CLL cell survival and suppresses BCR-mediated activation of C481S BTK and PLCγ2 mutants, which facilitate clinical resistance to ibrutinib. Significance: This study characterizes a rationally designed kinase inhibitor with efficacy in models recapitulating the most common mechanisms of acquired resistance to ibrutinib. Reversible BTK inhibition is a promising strategy to combat progressive CLL, and multikinase inhibition demonstrates superior efficacy to targeted ibrutinib therapy in the setting of Richter transformation. Cancer Discov; 8(10); 1300-15. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195 ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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3. BTK C481S -Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia.
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Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, Heerema NA, Zhao W, Coleman J, Jones D, Abruzzo L, Gordon A, Mantel R, Smith LL, McWhorter S, Davis M, Doong TJ, Ny F, Lucas M, Chase W, Jones JA, Flynn JM, Maddocks K, Rogers K, Jaglowski S, Andritsos LA, Awan FT, Blum KA, Grever MR, Lozanski G, Johnson AJ, and Byrd JC
- Subjects
- Adenine analogs & derivatives, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Phospholipase C gamma genetics, Piperidines, Protein-Tyrosine Kinases metabolism, Pyrazoles administration & dosage, Pyrazoles pharmacology, Pyrimidines administration & dosage, Pyrimidines pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Protein-Tyrosine Kinases genetics, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.
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- 2017
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4. Postibrutinib outcomes in patients with mantle cell lymphoma.
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Martin P, Maddocks K, Leonard JP, Ruan J, Goy A, Wagner-Johnston N, Rule S, Advani R, Iberri D, Phillips T, Spurgeon S, Kozin E, Noto K, Chen Z, Jurczak W, Auer R, Chmielowska E, Stilgenbauer S, Bloehdorn J, Portell C, Williams ME, Dreyling M, Barr PM, Chen-Kiang S, DiLiberto M, Furman RR, and Blum KA
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- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Mutation, Piperidines, Proportional Hazards Models, Protein-Tyrosine Kinases genetics, Retrospective Studies, Treatment Outcome, Lymphoma, Mantle-Cell drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
Despite unprecedented clinical activity in mantle cell lymphoma (MCL), primary and acquired resistance to ibrutinib is common. The outcomes and ideal management of patients who experience ibrutinib failure are unclear. We performed a retrospective cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 international sites. Medical records were evaluated for clinical characteristics, pathological and radiological data, and therapies used pre- and postibrutinib. A total of 114 subjects met eligibility criteria. The median number of prior therapies was 3 (range, 0-10). The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores at the start of ibrutinib were low, intermediate, and high in 46%, 31%, and 23% of patients, respectively. Of patients with available data prior to ibrutinib and postibrutinib, 34 of 47 and 11 of 12 had a Ki67 >30%. The median time on ibrutinib was 4.7 months (range 0.7-43.6). The median overall survival (OS) following cessation of ibrutinib was 2.9 months (95% confidence interval [CI], 1.6-4.9). Of the 104 patients with data available, 73 underwent subsequent treatment an average of 0.3 months after stopping ibrutinib with a median OS of 5.8 months (95% CI, 3.7-10.4). Multivariate Cox regression analysis of MIPI before postibrutinib treatment, and subsequent treatment with bendamustine, cytarabine, or lenalidomide failed to reveal any association with OS. Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance. We could not identify treatments that clearly improved outcomes. Future trials should focus on understanding the mechanisms of ibrutinib resistance and on treatment after ibrutinib., (© 2016 by The American Society of Hematology.)
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- 2016
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5. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.
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Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, Lacey SF, Melenhorst JJ, McGettigan SE, Cook DR, Zhang C, Xu J, Do P, Hulitt J, Kudchodkar SB, Cogdill AP, Gill S, Porter DL, Woyach JA, Long M, Johnson AJ, Maddocks K, Muthusamy N, Levine BL, June CH, Byrd JC, and Maus MV
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- Adenine analogs & derivatives, Administration, Oral, Aged, Animals, Antigens, CD metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cytotoxicity, Immunologic drug effects, Demography, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Gene Transfer Techniques, Humans, Immunosuppression Therapy, K562 Cells, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Mice, Middle Aged, Piperidines, Programmed Cell Death 1 Receptor metabolism, Pyrazoles administration & dosage, Pyrazoles pharmacology, Pyrimidines administration & dosage, Pyrimidines pharmacology, T-Lymphocytes drug effects, Time Factors, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology
- Abstract
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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6. Incidence and description of autoimmune cytopenias during treatment with ibrutinib for chronic lymphocytic leukemia.
- Author
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Rogers KA, Ruppert AS, Bingman A, Andritsos LA, Awan FT, Blum KA, Flynn JM, Jaglowski SM, Lozanski G, Maddocks KJ, Byrd JC, Woyach JA, and Jones JA
- Subjects
- Adenine analogs & derivatives, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, Anemia, Hemolytic, Autoimmune epidemiology, Female, Humans, Incidence, Male, Middle Aged, Piperidines, Purpura, Thrombocytopenic, Idiopathic epidemiology, Anemia, Hemolytic, Autoimmune chemically induced, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Protein-Tyrosine Kinases antagonists & inhibitors, Purpura, Thrombocytopenic, Idiopathic chemically induced, Pyrazoles adverse effects, Pyrimidines adverse effects
- Abstract
Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AICs). Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase approved for the treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib, as participants in therapeutic clinical trials at The Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment-emergent AIC cases were identified. Before starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment-emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment-emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.
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- 2016
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7. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation.
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Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S, Strattan E, Lehman A, Zhang X, Jones JA, Flynn J, Andritsos LA, Maddocks K, Jaglowski SM, Blum KA, Byrd JC, Dubovsky JA, and Johnson AJ
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cells, Cultured, Chickens, Drug Resistance, Neoplasm drug effects, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mutation, Missense, Piperidines, Protein-Tyrosine Kinases antagonists & inhibitors, Signal Transduction genetics, Syk Kinase, src-Family Kinases antagonists & inhibitors, Drug Resistance, Neoplasm genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Phospholipase C gamma genetics, Protein-Tyrosine Kinases physiology, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Receptors, Antigen, B-Cell metabolism
- Abstract
Ibrutinib has significantly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Recent reports attribute ibrutinib resistance to acquired mutations in Bruton agammaglobulinemia tyrosine kinase (BTK), the target of ibrutinib, as well as the immediate downstream effector phospholipase C, γ2 (PLCG2). Although the C481S mutation found in BTK has been shown to disable ibrutinib's capacity to irreversibly bind this primary target, the detailed mechanisms of mutations in PLCG2 have yet to be established. Herein, we characterize the enhanced signaling competence, BTK independence, and surface immunoglobulin dependence of the PLCG2 mutation at R665W, which has been documented in ibrutinib-resistant CLL. Our data demonstrate that this missense alteration elicits BTK-independent activation after B-cell receptor engagement, implying the formation of a novel BTK-bypass pathway. Consistent with previous results, PLCG2(R665W) confers hypermorphic induction of downstream signaling events. Our studies reveal that proximal kinases SYK and LYN are critical for the activation of mutant PLCG2 and that therapeutics targeting SYK and LYN can combat molecular resistance in cell line models and primary CLL cells from ibrutinib-resistant patients. Altogether, our results engender a molecular understanding of the identified aberration at PLCG2 and explore its functional dependency on BTK, SYK, and LYN, suggesting alternative strategies to combat acquired ibrutinib resistance., (© 2015 by The American Society of Hematology.)
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- 2015
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8. miR-155 expression is associated with chemoimmunotherapy outcome and is modulated by Bruton's tyrosine kinase inhibition with Ibrutinib.
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Guinn D, Ruppert AS, Maddocks K, Jaglowski S, Gordon A, Lin TS, Larson R, Marcucci G, Hertlein E, Woyach J, Johnson AJ, and Byrd JC
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- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Alemtuzumab, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Disease Progression, Disease-Free Survival, Gene Expression Regulation, Leukemic, Humans, Immunotherapy methods, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Multivariate Analysis, Piperidines, Rituximab, Treatment Outcome, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Antineoplastic Agents therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, MicroRNAs metabolism, Protein-Tyrosine Kinases metabolism, Pyrazoles therapeutic use, Pyrimidines therapeutic use
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- 2015
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9. Ibrutinib in B-cell Lymphomas.
- Author
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Maddocks K and Blum KA
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Boronic Acids therapeutic use, Bortezomib, Clinical Trials as Topic, Disease-Free Survival, Humans, Lenalidomide, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell therapy, Piperidines, Protein-Tyrosine Kinases metabolism, Pyrazines therapeutic use, Signal Transduction, Thalidomide analogs & derivatives, Thalidomide therapeutic use, Treatment Outcome, Antineoplastic Agents therapeutic use, Lymphoma, B-Cell drug therapy, Lymphoma, Follicular drug therapy, Pyrazoles therapeutic use, Pyrimidines therapeutic use
- Abstract
The standard frontline therapy for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) includes the use of chemoimmunotherapy and/or radiation therapy. When patients with these diseases relapse or are refractory to therapy, their diseases are considered incurable outside of the setting of an autologous or allogeneic stem cell transplant, which many patients are not candidates for due to age or comorbidities. The oral Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, targets the B-cell receptor (BCR) signaling pathway that is critical in the survival of these malignancies. It has shown promising activity in certain subtypes of DLBCL, in relapsed or refractory FL, and in relapsed or refractory MCL for which it has recently received FDA approval and should be considered for use in patients in first relapse. Ibrutinib is an oral therapy taken daily that has been well tolerated by patients. Given the high response rates, tolerability, and acceptable toxicities of ibrutinib therapy, it is now being evaluated in combination therapy both in relapsed B-cell malignancies and frontline studies in DLBCL and MCL. Several other promising agents targeting different kinases in the BCR signaling pathway also are currently under investigation.
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- 2014
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10. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy.
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Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS, Lucas D, Williams K, Zhao W, Rassenti L, Ghia E, Kipps TJ, Mantel R, Jones J, Flynn J, Maddocks K, O'Brien S, Furman RR, James DF, Clow F, Lozanski G, Johnson AJ, and Byrd JC
- Subjects
- Adenine analogs & derivatives, Adult, Agammaglobulinaemia Tyrosine Kinase, Aged, Aged, 80 and over, CD40 Ligand metabolism, Disease-Free Survival, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes metabolism, Lymphocytosis blood, Lymphocytosis immunology, Male, Middle Aged, Phospholipase C gamma antagonists & inhibitors, Phosphorylation, Piperidines, Prognosis, Protein Kinase Inhibitors adverse effects, Protein-Tyrosine Kinases antagonists & inhibitors, Receptors, Antigen, B-Cell metabolism, Signal Transduction drug effects, ZAP-70 Protein-Tyrosine Kinase metabolism, Lymphocytosis etiology, Pyrazoles adverse effects, Pyrimidines adverse effects
- Abstract
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has outstanding activity in patients with chronic lymphocytic leukemia. Most patients experience lymphocytosis, representing lymphocyte egress from nodal compartments. This resolves within 8 months in the majority of patients, but a subgroup has lymphocytosis lasting >12 months. Here we report a detailed characterization of patients with persistent lymphocytosis during ibrutinib therapy. Signaling evaluation showed that while BTK is inhibited, downstream mediators of B-cell receptor (BCR) signaling are activated in persistent lymphocytes. These cells cannot be stimulated through the BCR and do not show evidence of target gene activation. Flow cytometry for κ and λ expression, IGHV sequencing, Zap-70 methylation, and targeted gene sequencing in these patients are identical at baseline and later time points, suggesting that persistent lymphocytes do not represent clonal evolution. In vitro treatment with targeted kinase inhibitors shows that they are not addicted to a single survival pathway. Finally, progression-free survival is not inferior for patients with prolonged lymphocytosis vs those with traditional responses. Thus, prolonged lymphocytosis is common following ibrutinib treatment, likely represents the persistence of a quiescent clone, and does not predict a subgroup of patients likely to relapse early.
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- 2014
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11. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.
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Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, Hessler JD, Liu TM, Chang BY, Larkin KM, Stefanovski MR, Chappell DL, Frissora FW, Smith LL, Smucker KA, Flynn JM, Jones JA, Andritsos LA, Maddocks K, Lehman AM, Furman R, Sharman J, Mishra A, Caligiuri MA, Satoskar AR, Buggy JJ, Muthusamy N, Johnson AJ, and Byrd JC
- Subjects
- Adenine analogs & derivatives, Animals, CD8-Positive T-Lymphocytes cytology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes enzymology, Disease Models, Animal, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Humans, Jurkat Cells, Leishmaniasis, Cutaneous drug therapy, Leishmaniasis, Cutaneous immunology, Leukemia drug therapy, Leukemia immunology, Listeriosis drug therapy, Listeriosis immunology, Lymphocyte Activation drug effects, Mice, Piperidines, Primary Cell Culture, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Th1 Cells cytology, Th1 Cells enzymology, Th2 Cells cytology, Th2 Cells drug effects, Th2 Cells enzymology, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrimidines pharmacology, Th1 Cells drug effects
- Abstract
Given its critical role in T-cell signaling, interleukin-2-inducible kinase (ITK) is an appealing therapeutic target that can contribute to the pathogenesis of certain infectious, autoimmune, and neoplastic diseases. Ablation of ITK subverts Th2 immunity, thereby potentiating Th1-based immune responses. While small-molecule ITK inhibitors have been identified, none have demonstrated clinical utility. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with outstanding clinical activity and tolerability in B-cell malignancies. Significant homology between BTK and ITK alongside in silico docking studies support ibrutinib as an immunomodulatory inhibitor of both ITK and BTK. Our comprehensive molecular and phenotypic analysis confirms ITK as an irreversible T-cell target of ibrutinib. Using ibrutinib clinical trial samples along with well-characterized neoplastic (chronic lymphocytic leukemia), parasitic infection (Leishmania major), and infectious disease (Listeria monocytogenes) models, we establish ibrutinib as a clinically relevant and physiologically potent ITK inhibitor with broad therapeutic utility. This trial was registered at www.clinicaltrials.gov as #NCT01105247 and #NCT01217749.
- Published
- 2013
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