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1.
Br J Haematol ; 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32130737

RESUMO

Anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post-induction therapy, by enhancing antibody-dependent cellular cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised that ex vivo expanded lymphokine-activated killer (LAK) cells administered to FL-remission patients are safe and improve anti-CD20 efficacy. This open, prospective, phase II, single-arm study assessed safety and efficacy of ex vivo expanded LAK cells in 20 FL-remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL-2) for 8 weeks, after which >5 × 108 LAK cells were injected. Patients were followed-up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL-2 (rhIL-2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment-related serious adverse events. Three patients had progressed by the end of follow-up. After a median (interquartile range) follow-up of 59.4 (43.8-70.9) months, 85% of patients remained progression free. No deaths occurred. Quality-of-life improved throughout the study. Post-induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.

2.
Ann Hematol ; 99(4): 799-808, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32076827

RESUMO

Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population.

3.
Blood ; 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31977002

RESUMO

Treatment options for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) are limited with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose expansion study assessed safety and clinical activity of avadomide monotherapy in patients with R/R de novo DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 transformed lymphoma, received 3 to 5 mg of avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7­day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin-independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR versus an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.

4.
Br J Haematol ; 188(5): 661-673, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31573078

RESUMO

Rituximab is a standard treatment for non-Hodgkin diffuse large B-cell (DLBCL) and follicular (FL) lymphomas. A subcutaneous formulation was developed to improve the resource use of intravenous rituximab, with comparable efficacy and safety profiles except for increased administration-related reactions (ARRs). MabRella was a phase IIIb trial to assess the safety of switching from intravenous to subcutaneous administration of rituximab during first-line induction/maintenance for DLBCL or FL, focusing on ARRs. Efficacy, satisfaction and quality of life were also assessed. Patients received subcutaneous rituximab plus standard induction chemotherapy for DLBCL or FL for 4-7 cycles, and/or every 2 months maintenance monotherapy for FL for 6-12 cycles. The study included 140 patients: DLBCL, n = 29; FL, n = 111. Ninety-five percent of patients experienced adverse events, reaching grade ≥3 in 38·6% and were serious in 30·0%. AARs occurred in 48·6%, mostly (84·9%) at the injection site, with only 2·1% of patients reaching grade 3. The end-of-induction complete/unconfirmed complete response rate was 69·6%. After a median follow-up of 33·5 months, median disease-/event-/progression-free and overall survivals were not attained. The Rituximab Administration Satisfaction Questionnaire showed improvements in overall satisfaction and the EuroQoL-5D a good quality-of-life perception at induction/maintenance end. Therefore, switching to subcutaneous rituximab showed no new safety issues and maintained efficacy with improved satisfaction and quality of life.

5.
Future Sci OA ; 5(10): FSO425, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31827894

RESUMO

Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells.

7.
Blood ; 133(22): 2401-2412, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-30975638

RESUMO

Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-κB activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-κB and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion. Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-κB-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.


Assuntos
Linfócitos B/imunologia , Antígeno B7-H1/imunologia , Regulação Neoplásica da Expressão Gênica , Ativação Linfocitária , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral , Proteína Supressora de Tumor p53/imunologia , Animais , Linfócitos B/patologia , Antígeno B7-H1/genética , Feminino , Humanos , Imunoterapia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/genética , Linfócitos T/imunologia , Linfócitos T/patologia , Proteína Supressora de Tumor p53/genética
8.
Haematologica ; 104(9): 1822-1829, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30733272

RESUMO

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

9.
Clin Cancer Res ; 25(10): 3176-3187, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30692097

RESUMO

PURPOSE: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. EXPERIMENTAL DESIGN: We performed a comprehensive analysis of the MoA of isatuximab. RESULTS: Isatuximab induces internalization of CD38 but not its significant release from MM cell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38hi MM cells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38lo and CD38hi tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38hi MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38hi B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis. CONCLUSIONS: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38lo MM patients.See related commentary by Malavasi and Faini, p. 2946.


Assuntos
Mieloma Múltiplo/imunologia , ADP-Ribosil Ciclase 1/imunologia , Anticorpos Monoclonais , Humanos
10.
Oncotarget ; 9(64): 32383-32399, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30190794

RESUMO

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of non-Hodgkin lymphoma (NHL) cases in adult series. DLBCL is characterized by marked clinical and biological heterogeneity, encompassing up to 16 distinct clinicopathological entities. While current treatments are effective in 60% to 70% of patients, those who are resistant to treatment continue to die from this disease. An expert panel performed a systematic review of all data on the diagnosis, prognosis, and treatment of DLBCL published in PubMed, EMBASE and MEDLINE up to December 2017. Recommendations were classified in accordance with the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework, and the proposed recommendations incorporated into practical algorithms. Initial discussions between experts began in March 2016, and a final consensus was reached in November 2017. The final document was reviewed by all authors in February 2018 and by the Scientific Committee of the Spanish Lymphoma Group GELTAMO.

11.
Curr Opin Nephrol Hypertens ; 27(6): 440-444, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30157079

RESUMO

PURPOSE OF REVIEW: Posttransplant lymphoproliferative disorder (PTLD), frequently associated with Epstein-Barr virus (EBV), is one of the most serious complications leading to worse patient and graft outcomes. Hence, we summarize in this review relevant studies published about PTLD in the last 18 months. RECENT FINDINGS: Recent studies have improved the knowledge about epidemiology, prophylaxis, diagnosis and PTLD treatment. Special interest has developed in improving the last PTLD classification of the World Health Organization, increasing the accuracy of diagnostic tests for EBV viral load quantification and discriminating the genetic differences between PTLD types. There seems to be no real advantage in the use of antiviral drugs for prophylaxis, but better results in therapeutic approaches are being obtained mainly with the use of rituximab with or without chemotherapy, but also with the possibility of using adoptive T-cell therapy or new drugs. SUMMARY: PTLD continues being a complication that requires continued effort of the scientific community to reduce its incidence and to develop better diagnostic tests and new strategies that improve results in prophylaxis and treatment.


Assuntos
Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Complicações Pós-Operatórias/terapia , Antivirais/uso terapêutico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/epidemiologia , Complicações Pós-Operatórias/tratamento farmacológico
12.
Leuk Lymphoma ; 59(12): 2888-2895, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29846137

RESUMO

This was an open-label, multicenter, phase-1 study to evaluate the drug interaction between steady-state ibrutinib and moderate (erythromycin) and strong (voriconazole) CYP3A inhibitors in patients with B-cell malignancies and to confirm dosing recommendations. During cycle 1, patients received oral ibrutinib 560 mg qd alone (Days 1-4 and 14-18), and ibrutinib 140 mg (Days 5-13; 19-27) plus erythromycin 500 mg tid (Days 5-11) and voriconazole 200 mg bid (Days 19-25). Twenty-six patients (median [range] age: 64.5 [50-88] years) were enrolled. Geometric mean ratio (90% confidence intervals) after co-administration of ibrutinib 140 mg with erythromycin and voriconazole was 74.7 (53.97-103.51) and 143.3 (107.77-190.42), respectively, versus ibrutinib 560 mg alone. The most common (≥20%) adverse events were diarrhea (27%) and neutropenia (23%). The results demonstrate that ibrutinib 140 mg with voriconazole or erythromycin provides exposure within the clinical range for patients with B-cell malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linfócitos B/patologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Pirazóis/farmacologia , Pirimidinas/farmacologia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações de Medicamentos , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Polimorfismo de Nucleotídeo Único , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Voriconazol/farmacologia , Voriconazol/uso terapêutico
13.
Immunotherapy ; 10(6): 491-499, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29562857

RESUMO

AIM: Obinutuzumab induces NK cell antibody-dependent cell-mediated cytotoxicity. OBJECTIVE: Investigate the effects on the human immune system after obinutuzumab monotherapy treatment in patients with chronic lymphocytic leukemia (CLL). METHOD: To evaluate these effects, we analyzed the distribution of CD4+ and CD8+ T cells, B cells and NK cells in the peripheral blood of eight CLL patients who were treated with obinutuzumab in monotherapy. The distribution of peripheral blood lymphocytes was examined prior to each dose of obinutuzumab and 24-72 h after the first 1000 mg complete dose (cycle 1 day 2). We also repeated measurements 3 months after the last obinutuzumab dose. In total we obtained ten samples of each patient. Analyses were performed by flow cytometry with monoclonal antibodies against CD3, CD4, CD8, CD19 and CD56+. RESULTS: After the first 1000 mg obinutuzumab infusion (cycle 1 day 2), CD4+ T cells and CD8+ T cells were significantly decreased in peripheral blood compared with prior to therapy. This reduction in the CD4+ T cells persisted after six cycles of obinutuzumab (1235 cells/µl basal vs 662 cells/µl after six cycles, p ≤ 0.05), but not in CD8+ T cells (987 cells/µl basal vs 837 cells/µl after six cycles). Interestingly, we also observed significant differences in the NK cell compartment after the first 1000 mg drug infusion (490 cells/µl basal vs 23 cells/µl postinfusion, p ≤ 0.05), and after cycle 6 (490 cells/µl basal vs 149 cells/µl after six cycles, p ≤ 0.05). CONCLUSION: Obinutuzumab induces depletion of NK cells in CLL.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Celular Dependente de Anticorpos , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Depleção Linfocítica , Masculino
14.
J Pathol ; 245(1): 61-73, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29464716

RESUMO

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2-/- IL2γc-/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Imunossupressores/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Transformação Celular Neoplásica/patologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade
16.
Rev Esp Enferm Dig ; 110(2): 131-132, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29313699

RESUMO

We have read the article "Post-transplant lymphoproliferative disease in liver transplant recipients" with great interest. This article reports a series of liver transplant recipients with post-transplant lymphoproliferative disease (PTLD). The effect on patient survival and the potential benefit of rituximab-based therapy are highlighted. Rituximab is a chimeric antibody against the CD20 surface marker. This marker is found in most PTLD of a B cell origin. A recent study from our center also highlighted the role of rituximab in PTLD therapy (3). The overall response rate of patients treated with rituximab was 66% in both series. In our series, this included heart, kidney and liver transplant recipients. Rituximab-based therapy was also associated with an increased overall survival. Rituximab should be considered as part of the first-line therapy in patients with PTLD when CD20 expression is present.


Assuntos
Transplante de Fígado , Transtornos Linfoproliferativos , Infecções por Vírus Epstein-Barr , Humanos , Linfoma , Rituximab
17.
Haematologica ; 103(6): 1065-1072, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29191842

RESUMO

Regulatory T (Treg) cells can weaken antitumor immune responses, and inhibition of their function appears to be a promising therapeutic approach in cancer patients. Mice with targeted deletion of the gene encoding the Cl-/HCO3- anion exchanger AE2 (also termed SLC4A2), a membrane-bound carrier involved in intracellular pH regulation, showed a progressive decrease in the number of Treg cells. We therefore challenged AE2 as a potential target for tumor therapy, and generated linear peptides designed to bind the third extracellular loop of AE2, which is crucial for its exchange activity. Peptide p17AE2 exhibited optimal interaction ability and indeed promoted apoptosis in mouse and human Treg cells, while activating effector T-cell function. Interestingly, this linear peptide also induced apoptosis in different types of human leukemia, lymphoma and multiple myeloma cell lines and primary malignant samples, while it showed only moderate effects on normal B lymphocytes. Finally, a macrocyclic AE2 targeting peptide exhibiting increased stability in vivo was effective in mice xenografted with B-cell lymphoma. These data suggest that targeting the anion exchanger AE2 with specific peptides may represent an effective therapeutic approach in B-cell malignancies.


Assuntos
Antineoplásicos/farmacologia , Antiportadores de Cloreto-Bicarbonato/antagonistas & inibidores , Leucemia de Células B/metabolismo , Linfoma de Células B/metabolismo , Peptídeos/farmacologia , Animais , Ânions/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Leucemia de Células B/tratamento farmacológico , Leucemia de Células B/patologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Lancet ; 391(10121): 659-667, 2018 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-29241979

RESUMO

BACKGROUND: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. METHODS: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. FINDINGS: From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). INTERPRETATION: Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population. FUNDING: Acerta Pharma, a member of the AstraZeneca Group.


Assuntos
Benzamidas/administração & dosagem , Linfoma de Célula do Manto/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirazinas/administração & dosagem , Idoso , Benzamidas/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/efeitos adversos , Recidiva , Análise de Sobrevida , Resultado do Tratamento
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