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1.
J Cell Sci ; 133(5)2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32005699

RESUMO

Phagocytosis is a dynamic process central to immunity and tissue homeostasis. Current methods for quantification of phagocytosis largely rely on indirect or static measurements, such as target clearance or dye uptake, and thus provide limited information about engulfment rates or target processing. Improved kinetic measurements of phagocytosis could provide useful, basic insights in many areas. We present a live-cell, time-lapse and high-content microscopy imaging method based on the detection and quantification of fluorescent dye 'voids' within phagocytes that result from target internalization to quantify phagocytic events with high temporal resolution. Using this method, we measure target cell densities and antibody concentrations needed for optimal antibody-dependent cellular phagocytosis. We compare void formation and dye uptake methods for phagocytosis detection, and examine the connection between target cell engulfment and phagolysosomal processing. We demonstrate how this approach can be used to measure distinct forms of phagocytosis, and changes in macrophage morphology during phagocytosis related to both engulfment and target degradation. Our results provide a high-resolution method for quantifying phagocytosis that provides opportunities to better understand the cellular and molecular regulation of this fundamental biological process.


Assuntos
Microscopia , Fagócitos , Macrófagos , Fagocitose , Imagem com Lapso de Tempo
2.
Blood ; 136(18): 2065-2079, 2020 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-32556153

RESUMO

Macrophage antibody (Ab)-dependent cellular phagocytosis (ADCP) is a major cytotoxic mechanism for both therapeutic unconjugated monoclonal Abs (mAbs) such as rituximab and Ab-induced hemolytic anemia and immune thrombocytopenia. Here, we studied the mechanisms controlling the rate and capacity of macrophages to carry out ADCP in settings of high target/effector cell ratios, such as those seen in patients with circulating tumor burden in leukemic phase disease. Using quantitative live-cell imaging of primary human and mouse macrophages, we found that, upon initial challenge with mAb-opsonized lymphocytes, macrophages underwent a brief burst (<1 hour) of rapid phagocytosis, which was then invariably followed by a sharp reduction in phagocytic activity that could persist for days. This previously unknown refractory period of ADCP, or hypophagia, was observed in all macrophage, mAb, and target cell conditions tested in vitro and was also seen in vivo in Kupffer cells from mice induced to undergo successive rounds of αCD20 mAb-dependent clearance of circulating B cells. Importantly, hypophagia had no effect on Ab-independent phagocytosis and did not alter macrophage viability. In mechanistic studies, we found that the rapid loss of activating Fc receptors from the surface and their subsequent proteolytic degradation were the primary mechanisms responsible for the loss of ADCP activity in hypophagia. These data suggest hypophagia is a critical limiting step in macrophage-mediated clearance of cells via ADCP, and understanding such limitations to innate immune system cytotoxic capacity will aid in the development of mAb regimens that could optimize ADCP and improve patient outcome.


Assuntos
Anticorpos Monoclonais/farmacologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Imunidade Inata/efeitos dos fármacos , Macrófagos/patologia , Fagócitos/imunologia , Fagocitose , Rituximab/farmacologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Feminino , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagócitos/efeitos dos fármacos
4.
Blood ; 132(22): 2389-2400, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30213873

RESUMO

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.


Assuntos
Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/genética , MicroRNAs/genética , Proteínas Repressoras/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Ativação Transcricional , Regulação para Cima
5.
Blood ; 129(5): 553-560, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-27903528

RESUMO

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.


Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/tratamento farmacológico , Pentostatina/uso terapêutico , Gerenciamento Clínico , Humanos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Resultado do Tratamento
6.
Haematologica ; 104(9): 1841-1852, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30792198

RESUMO

CD20 monoclonal antibody therapies have significantly improved the outlook for patients with B-cell malignancies. However, many patients acquire resistance, demonstrating the need for new and improved drugs. We previously demonstrated that the natural process of antibody hexamer formation on targeted cells allows for optimal induction of complement-dependent cytotoxicity. Complement-dependent cytotoxicity can be potentiated by introducing a single point mutation such as E430G in the IgG Fc domain that enhances intermolecular Fc-Fc interactions between cell-bound IgG molecules, thereby facilitating IgG hexamer formation. Antibodies specific for CD37, a target that is abundantly expressed on healthy and malignant B cells, are generally poor inducers of complement-dependent cytotoxicity. Here we demonstrate that introduction of the hexamerization-enhancing mutation E430G in CD37-specific antibodies facilitates highly potent complement-dependent cytotoxicity in chronic lymphocytic leukemia cells ex vivo Strikingly, we observed that combinations of hexamerization-enhanced CD20 and CD37 antibodies cooperated in C1q binding and induced superior and synergistic complement-dependent cytotoxicity in patient-derived cancer cells compared to the single agents. Furthermore, CD20 and CD37 antibodies colocalized on the cell membrane, an effect that was potentiated by the hexamerization-enhancing mutation. Moreover, upon cell surface binding, CD20 and CD37 antibodies were shown to form mixed hexameric antibody complexes consisting of both antibodies each bound to their own cognate target, so-called hetero-hexamers. These findings provide novel insights into the mechanisms of synergy in antibody-mediated complement-dependent cytotoxicity and provide a rationale to explore Fc-engineering and antibody hetero-hexamerization as a tool to enhance the cooperativity and therapeutic efficacy of antibody combinations.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antígenos CD20/imunologia , Antígenos de Neoplasias/imunologia , Proteínas do Sistema Complemento/imunologia , Fragmentos Fc das Imunoglobulinas/imunologia , Leucemia Linfocítica Crônica de Células B/genética , Tetraspaninas/imunologia , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Linhagem Celular Tumoral , Complemento C1q/imunologia , Transferência Ressonante de Energia de Fluorescência , Humanos , Imunoglobulina G/imunologia , Leucemia Linfocítica Crônica de Células B/sangue , Mutação , Ligação Proteica , Rituximab/farmacologia
7.
Blood ; 128(18): 2199-2205, 2016 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-27601462

RESUMO

B-cell receptor kinase inhibitor (KI) therapy represents a paradigm shift in chronic lymphocytic leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 patients with CLL (ibrutinib = 143; idelalisib = 35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%). Overall response rate (ORR) to first KI was 62% (complete response 14%). The most common reasons for KI discontinuation were toxicity (51%), CLL progression (29%), and Richter transformation (RT) (8%). Median progression-free survival (PFS) and OS from KI initiation were 10.5 and 29 months, respectively. Notably, initial KI choice did not impact PFS or OS; however, RT portended significantly inferior OS (P = .0007). One hundred fourteen patients received subsequent salvage therapy following KI discontinuation with an ORR to subsequent KI at 50% and a median PFS of 11.9 months. Median PFS in KI-intolerant patients treated with an alternate KI was not reached vs 7 months for patients with CLL progression. In summary, these data demonstrate that toxicity was the most common reason for KI discontinuation, that patients who discontinue KI due to toxicity can respond to an alternate KI, and that these responses may be durable. This trial was registered at www.clinicaltrials.gov as #NCT02717611 and #NCT02742090.


Assuntos
Antineoplásicos/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Quinazolinonas/administração & dosagem , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Estudos de Coortes , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Piperidinas , Modelos de Riscos Proporcionais , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Quinazolinonas/efeitos adversos , Estudos Retrospectivos , Terapia de Salvação/métodos , Terapia de Salvação/mortalidade , Resultado do Tratamento
8.
Haematologica ; 103(9): 1511-1517, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29880613

RESUMO

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Síndrome de Lise Tumoral/etiologia
11.
Am J Hematol ; 93(11): 1394-1401, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30132965

RESUMO

Ibrutinib demonstrated superior response rates and survival for treatment-naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 (<65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically <65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front-line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE-2 trial: <65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty-one percent of our cohort was <65, and 30% had del(17p13). Patients <65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty-four percent discontinued ibrutinib at 13.8 months median follow-up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in <65 and those with del(17p13). Response rates were similar for <65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front-line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE-2.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Fatores Etários , Idoso , Cromossomos Humanos Par 17/genética , Ensaios Clínicos como Assunto , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Piperidinas , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Indução de Remissão , Estudos Retrospectivos , Deleção de Sequência , Análise de Sobrevida , Resultado do Tratamento
12.
J Immunol ; 197(5): 1762-75, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27474078

RESUMO

Recently, we demonstrated that IgG Abs can organize into ordered hexamers after binding their cognate Ags expressed on cell surfaces. This process is dependent on Fc:Fc interactions, which promote C1q binding, the first step in classical pathway complement activation. We went on to engineer point mutations that stimulated IgG hexamer formation and complement-dependent cytotoxicity (CDC). The hexamer formation-enhanced (HexaBody) CD20 and CD38 mAbs support faster, more robust CDC than their wild-type counterparts. To further investigate the CDC potential of these mAbs, we used flow cytometry, high-resolution digital imaging, and four-color confocal microscopy to examine their activity against B cell lines and primary chronic lymphocytic leukemia cells in sera depleted of single complement components. We also examined the CDC activity of alemtuzumab (anti-CD52) and mAb W6/32 (anti-HLA), which bind at high density to cells and promote substantial complement activation. Although we observed little CDC for mAb-opsonized cells reacted with sera depleted of early complement components, we were surprised to discover that the Hexabody mAbs, as well as ALM and W6/32, were all quite effective at promoting CDC in sera depleted of individual complement components C6 to C9. However, neutralization studies conducted with an anti-C9 mAb verified that C9 is required for CDC activity against cell lines. These highly effective complement-activating mAbs efficiently focus activated complement components on the cell, including C3b and C9, and promote CDC with a very low threshold of MAC binding, thus providing additional insight into their enhanced efficacy in promoting CDC.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD20/metabolismo , Antígenos/imunologia , Sítios de Ligação de Anticorpos , Complemento C9/metabolismo , Glicoproteínas de Membrana/metabolismo , ADP-Ribosil Ciclase 1/imunologia , Alemtuzumab , Anticorpos Monoclonais Humanizados/imunologia , Antígenos CD20/imunologia , Linfócitos B/imunologia , Linhagem Celular Tumoral , Ativação do Complemento , Complemento C3b/metabolismo , Complemento C9/imunologia , Proteínas do Sistema Complemento/imunologia , Proteínas do Sistema Complemento/metabolismo , Humanos , Glicoproteínas de Membrana/imunologia
13.
Clin Immunol ; 181: 24-28, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28578024

RESUMO

We examined complement-dependent cytotoxicity (CDC) by hexamer formation-enhanced CD20 mAb Hx-7D8 of patient-derived chronic lymphocytic leukemia (CLL) cells that are relatively resistant to CDC. CDC was analyzed in normal human serum (NHS) and serum from an individual genetically deficient for C9. Hx-7D8 was able to kill up to 80% of CLL cells in complete absence of C9. We conclude that the narrow C5b-8 pores formed without C9 are sufficient for CDC due to efficient antibody-mediated hexamer formation. In the absence of C9, we observed transient intracellular increases of Ca2+ during CDC (as assessed with FLUO-4) that were extended in time. This suggests that small C5b-8 pores allow Ca2+ to enter the cell, while dissipation of the fluorescent signal accompanying cell disintegration is delayed. The Ca2+ signal is retained concomitantly with TOPRO-3 (viability dye) staining, thereby confirming that Ca2+ influx represents the most proximate mediator of cell death by CDC.


Assuntos
Complemento C9/deficiência , Proteínas do Sistema Complemento/imunologia , Síndromes de Imunodeficiência/imunologia , Leucemia Linfocítica Crônica de Células B , Rituximab/farmacologia , Cálcio/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Complemento C9/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/metabolismo , Doenças da Deficiência Hereditária de Complemento , Humanos , Imunoterapia , Polimerização
15.
Br J Haematol ; 174(6): 835-46, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27391367

RESUMO

Cancer-related cognitive impairment (CRCI) is an important clinical problem for cancer patients and survivors. In this review, we summarize studies investigating the occurrence of impaired cognition in patients with haematological malignancies. Most published studies focus on survivors of childhood acute lymphoblastic leukaemia and primary central nervous system lymphoma. We also discuss studies conducted in acute myeloid leukaemia, myelodysplastic syndromes, chronic myeloid leukaemia, Hodgkin lymphoma (HL), non-HL and chronic lymphocytic leukaemia. Although research in this area is still emerging, it appears that a subset of chemotherapy-treated haematological malignancy survivors experience CRCI. Future research should focus on expanding the literature reviewed here with larger studies appropriately powered to assess cognition via objective and subjective measures in a longitudinal fashion to tease apart the impact of disease and the various forms of cancer treatment.


Assuntos
Antineoplásicos/efeitos adversos , Disfunção Cognitiva/etiologia , Neoplasias Hematológicas/complicações , Animais , Antineoplásicos/uso terapêutico , Cognição/efeitos dos fármacos , Cognição/efeitos da radiação , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/terapia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Gerenciamento Clínico , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/epidemiologia , Humanos , Fatores de Risco
16.
Am J Hematol ; 91(3): 308-12, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26662208

RESUMO

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients requiring initial therapy are often older and frailer and unsuitable candidates for standard chemoimmunotherapy regimens. Shorter duration combination monoclonal antibody (mAb) therapy using alemtuzumab and rituximab has been shown to be effective and tolerable treatment for CLL. Standard dose anti-CD20 mAb therapy causes loss of CD20 expression by surviving CLL cells, which can be minimized by decreasing the mAb dose. We report a randomized phase II clinical trial enrolling older (≥ 65 years) patients (median age 76 years, n = 31) with treatment naïve progressive CLL. Patients received 8-12 weeks of standard subcutaneous alemtuzumab with either intravenous standard (375 mg/m(2) weekly)(n = 16) or low dose (20 mg/m(2) 3x week)(n = 15) rituximab. This study was closed before full accrual because the manufacturer withdrew alemtuzumab for treatment of CLL. The overall response rate was 90% with an 45% complete response rate, median progression-free survival of 17.9 months and no significant differences in outcome between the low and standard dose rituximab arms. The major toxicities were cytopenia and infection with one treatment fatality caused by progressive multifocal leukoencephalopathy but no other opportunistic infections. Combination mAb therapy was effective and tolerable treatment for older and frailer patients with progressive CLL, achieving a high rate of complete remissions. These data support the role of mAb in therapy for less fit CLL patients and the further study of low dose higher frequency anti-CD20 mAb therapy as a potentially more effective use of anti-CD20 mAb in the treatment of CLL.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Rituximab/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Rituximab/administração & dosagem , Rituximab/efeitos adversos
17.
J Immunol ; 192(4): 1620-9, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24431228

RESUMO

Ofatumumab (OFA), a human CD20-targeting mAb, kills B lymphocytes using the innate immune system including complement-dependent cytotoxicity (CDC). The efficacy of OFA in patients with chronic lymphocytic leukemia (CLL) is limited by drug resistance, which is not well characterized. To better understand mechanisms of resistance, we prospectively studied CLL cells isolated from blood samples collected before and after in vivo exposure to the initial dose of OFA therapy in 25 patients undergoing their first treatment for progressive CLL. As previously reported, OFA therapy rapidly decreased the absolute lymphocyte count, CD20 expression by CLL cells, and serum complement levels. We now show that after administration of the first dose of OFA, there was a modest rebound in the absolute lymphocyte count and serum complement levels, but substantial ongoing loss of CD20 expression by CLL cells. These post-OFA treatment CLL cells were highly resistant to OFA-mediated CDC but retained sensitivity to alemtuzumab-mediated CDC in vitro. Posttherapy serum OFA levels correlated inversely with both the amount of pretreatment circulating cell-bound CD20 and with the decrease in this value following treatment. In vitro OFA-mediated CDC did not predict clinical responses, and the patients with first-dose reactions to OFA did not have markers of increased complement activation in vivo. We propose that optimal efficacy of CD20- targeted therapy for CLL requires determining an mAb dose size and frequency that optimizes CLL killing without exceeding the capacity of the cytotoxic mechanisms and thus minimizes loss of CD20 expression in the surviving CLL cells.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Linfócitos B/imunologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/biossíntese , Antígenos CD20/biossíntese , Antígenos CD20/sangue , Antígenos de Neoplasias/biossíntese , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Antígeno CD52 , Proteínas do Sistema Complemento/metabolismo , Ciclofosfamida/uso terapêutico , Citotoxicidade Imunológica/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Glicoproteínas/biossíntese , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pentostatina/uso terapêutico , Resultado do Tratamento
18.
Blood ; 121(20): 4137-41, 2013 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-23493782

RESUMO

Immunotherapy that facilitates endogenous T-cell activity has the potential to target therapy-resistant tumor clones. In vitro studies have demonstrated that lenalidomide repairs the T-cell immunologic synapse defect in chronic lymphocytic leukemia (CLL). Pentostatin, cyclophosphamide, and rituximab (PCR) in CLL is clinically active with modest toxicity, indicating suitability of this chemoimmunotherapy (CIT) platform for combination with immunotherapy. Here we report on a trial of PCR followed by lenalidomide consolidation. Of 34 patients who received lenalidomide, 24% improved their quality of response and 4 patients converted to minimal residual disease negative status. Retrospective comparison to a historical PCR trial indicated that lenalidomide consolidation extends time to progression requiring salvage therapy. Longitudinal analysis showed that antitumor T-cell immune synapse activity improved post-PCR and was further enhanced after lenalidomide consolidation. These novel data showing repair of T-cell defects provide proof-of-principle that lenalidomide-based consolidation after CIT could have a beneficial clinical and immunologic role in CLL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Consolidação , Sinapses Imunológicas/fisiologia , Imunoterapia , Leucemia Linfocítica Crônica de Células B/terapia , Linfócitos T/imunologia , Talidomida/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estudos de Coortes , Terapia Combinada , Humanos , Sinapses Imunológicas/efeitos dos fármacos , Imunoterapia/métodos , Lenalidomida , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Terapia Neoadjuvante , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/imunologia , Estudos Retrospectivos , Linfócitos T/efeitos dos fármacos , Linfócitos T/patologia , Talidomida/administração & dosagem , Fatores de Tempo , Resultado do Tratamento
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