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2.
Gulf J Oncolog ; 1(33): 7-18, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32476644

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has become a public health emergency of major international concern. In December 2019, an outbreak of atypical pneumonia known as COVID-19 was identified in Wuhan, China. The newly identified zoonotic coronavirus, severe acute respiratory syndrome coronavirus-2 (SARSCoV-2), is characterized by rapid human-to-human transmission. Acute lymphoblastic leukemia (ALL) patients are often in need for intensive chemotherapy to induce remission that will be complicated with prolonged period of cytopenias. They are often recalled to the hospital for treatment and disease surveillance. These patients may be immunocompromised due to the underlying malignancy or anti-cancer therapy. ALL patients are at higher risk of developing life-threatening infections. Several factors increase the risk of infection and the presence of multiple risk factors in the same patient is common. Cancer patients had an estimated 2-fold increased risk of contracting SARS-CoV-2 than the general population. With the World Health Organization declaring the novel coronavirus outbreak a pandemic, there is an urgent need to address the impact of such pandemic on ALL patients. This include changes to resource allocation, clinical care, and the consent process during a pandemic. Currently and due to limited data, there are no international guidelines to address the optimal management of ALL patients in any infectious pandemic. In this review, we will address the potential challenges associated with managing ALL patients during the COVID-19 infection pandemic with suggestions of some practical approaches, focusing on screening asymptomatic ALL patients, diagnostic and response evaluation and choice of chemotherapy in different scenarios and setting and use of hematopoietic stem cell transplantation (HSCT).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hospedeiro Imunocomprometido , Infecções Oportunistas/virologia , Pneumonia Viral/virologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Betacoronavirus/imunologia , Tomada de Decisão Clínica , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/transmissão , Procedimentos Clínicos , Técnicas de Apoio para a Decisão , Humanos , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/transmissão , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Pneumonia Viral/transmissão , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Medição de Risco , Fatores de Risco
3.
Mol Immunol ; 124: 1-8, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32480291

RESUMO

Regulatory T cells (Tregs) is one of the immunosuppressive subsets of CD4+ T cells characterized by transcription factor forkhead box protein P3 (FOXP3) expression which are involved in tumor development and progression. Identification of the factors that influence Treg cell function is extremely important. Our current study aimed to evaluate the frequency of Treg cells, cytokine secretion and the expression of microRNAs (miRNAs) in pediatric acute lymphoblastic leukemia (ALL) patients. The frequency of CD3+, CD4+ and CD4+CD25+FOXP3+ Treg was assessed by flow cytometry in 43 ALL patients versus 42 controls. Plasma levels of IL-10, transcription factor ß (TGF-ß), IL-6, IL-17, IL-23 and tumor necrosis factor (TNF-α) were measured by Enzyme-linked immunosorbent assay (ELISA). miR-21, miR-24, miR-26a, miR133b, miR-148a and miR-155 expression were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A slight insignificant increase in Treg cells in ALL patients compared to controls was observed. There was a significant elevation in IL-10 (p < 0.05), IL-6 (p < 0.01), IL-23 (p < 0.05) and TNF-α (p < 0.01) in ALL patients compared with controls. Meanwhile, a significant reduction in TGF-ß (p < 0.001) was recorded. A slight insignificant decrease in IL-17 in ALL patients was observed.ALL patients showed a significant increase in miR-21 (p < 0.05), miR-148a (p < 0.01), miR-24 (p < 0.05) and a significant reduction in miR-155 (p < 0.01). In conclusion, the slight change in Treg cells frequency and alteration in related cytokines could possibly involve in the pathogenesis of ALL. Dysregulated miRNAs, as a regulatory mechanism of epigenetics, might contribute to these observed results. Further researches are required to confirm our interesting findings.


Assuntos
Citocinas/imunologia , MicroRNAs/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/imunologia , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
4.
J Cancer Res Ther ; 16(1): 105-109, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32362618

RESUMO

Background: Aberrant phenotypes in acute leukemia have been reported with varying frequencies in independent studies and their association with prognostic factors is still a matter of debate. Aim: This study aims to identify the frequency of aberrant immunophenotypes in de novo acute myeloid leukemia (AML) and to evaluate their association with initial clinical and hematological features. Materials and Methods: A total of 181 patients of de novo AML were included during the time (July 2010-June 2012). The immunophenotype of all cases of AML was studied by using flow cytometry. Results: Aberrant lymphoid antigen expression was seen in 43.1% cases. Most frequent aberrant lymphoid antigen was CD7, seen in 26.5% cases. All French-American-British (FAB) subtypes except AML-M3 expressed aberrant lymphoid antigens. The expression was most common in AML-M4 in the current study. CD34 expression in AMLs was significantly associated with the expression of aberrant lymphoid antigens. Lymphoid antigen expression in adult AML was significantly associated with higher white blood cell (WBC) count (>50,000/mm3) and higher number of peripheral blasts (>70%). Conclusion: In summary, CD7 is the most common aberrant lymphoid antigen expressed in AML. FAB subtype AML-M3 is usually not associated with aberrant lymphoid antigen expression. AML cases with CD34 positivity are more likely to express aberrant lymphoid markers. The current study also supports that aberrant lymphoid antigen expression in adult AML is associated with adverse presenting hematological features (WBC count >50,000/mm3, peripheral blasts >70%). Pediatric Ly + AML cases are not associated with adverse presenting clinical and biological features.


Assuntos
Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/imunologia , Imunofenotipagem/métodos , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/imunologia , Antígenos CD34/metabolismo , Antígenos CD7/imunologia , Antígenos CD7/metabolismo , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prognóstico , Estudos Prospectivos , Centros de Atenção Terciária , Adulto Jovem
5.
Biochim Biophys Acta Gene Regul Mech ; 1863(8): 194564, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32376390

RESUMO

Advances in treatment of childhood leukaemia has led to vastly improved survival rates, however some subtypes such as those characterised by MLL gene rearrangement (MLL-r), especially in infants, continue to have high relapse rates and poor survival. Natural history and molecular studies indicate that infant acute lymphoblastic leukaemia (ALL) originates in utero, is distinct from childhood ALL, and most cases are caused by MLL-r resulting in an oncogenic MLL fusion protein. Unlike childhood ALL, only a very small number of additional mutations are present in infant ALL, indicating that MLL-r alone may be sufficient to give rise to this rapid onset, aggressive leukaemia in an appropriate fetal cell context. Despite modifications in treatment approaches, the outcome of MLL-r infant ALL has remained dismal and a clear understanding of the underlying biology of the disease is required in order to develop appropriate disease models and more effective therapeutic strategies.


Assuntos
Proteína de Leucina Linfoide-Mieloide/genética , Proteína de Leucina Linfoide-Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Animais , Linhagem Celular Tumoral , Metilação de DNA , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Recém-Nascido , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia
6.
Cancer Immunol Immunother ; 69(10): 2139-2145, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451682

RESUMO

B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.


Assuntos
Antígenos CD19/imunologia , Receptor do Fator Ativador de Células B/antagonistas & inibidores , Receptor do Fator Ativador de Células B/imunologia , Linfócitos B/imunologia , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Animais , Ensaios Clínicos Fase I como Assunto , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
7.
Nat Rev Clin Oncol ; 17(7): 418-434, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32242094

RESUMO

Immuno-oncology approaches have entered clinical practice, with tremendous progress particularly in the field of T cell-engaging therapies over the past decade. Herein, we provide an overview of the current status of bispecific T cell engager (BiTE) therapy, considering the unprecedented new indication for such therapy in combating minimal (or measurable) residual disease in patients with acute lymphoblastic leukaemia, and the development of novel approaches based on this concept. Key aspects that we discuss include the current clinical data, challenges relating to treatment administration and patient monitoring, toxicities and resistance to treatment, and novel strategies to overcome these hurdles as well as to broaden the indications for BiTE therapy, particularly to common solid cancers. Elucidation of mechanisms of resistance and immune escape and new technologies used in drug development pave the way for new and more-effective therapies and rational combinatorial approaches. In particular, we highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells (CART.BiTE cells), designed to integrate various immune functions into one molecule or a single cellular vector and thereby enhance efficacy without compromising safety. We also discuss the targeting of intracellular tumour-associated epitopes using bispecific constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which might broaden the armamentarium of T cell-engaging therapies.


Assuntos
Imunoterapia Adotiva , Imunoterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Anticorpos Biespecíficos/imunologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/imunologia
8.
Iran J Immunol ; 17(1): 87-93, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32224544

RESUMO

BACKGROUND: Drugs used in cancer treatment specifically kill T regulatory cells. OBJECTIVE: To determine different phenotypes of T regulatory cells during the maintenance phase chemotherapy for pediatric acute lymphoblastic leukemia (ALL). MATERIALS: We evaluated the percentages of regulatory T cells by flow cytometry. Soluble CTLA-4 (sCTLA-4) in plasma was evaluated by ELISA assay. RESULTS: Increased percentages of CD4+CD25+ T cells, CD4+CD39+ T cells, CD4+Foxp3+ T cells, and CD4+CD25High T cells were observed in children with ALL in comparison to healthy controls. In addition, the ALL patients with >12 months of therapy showed increased CD4+CD39+ T cells compared to the ALL patients with ≤12 months and healthy controls. Similarly, the CD4+CD25+ T cells and CD4+Foxp3+ T cells increased according to maintenance therapy time. CONCLUSION: Our results showed increased percentages of regulatory T cells in pediatric ALL patients despite chemotherapy, which might be compromising the anti-leukemic cellular immune response.


Assuntos
Quimioterapia de Manutenção/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Hidrocortisona/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Vincristina/uso terapêutico
9.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32152221

RESUMO

BACKGROUND: CD19 chimeric antigen receptor T (CAR-T) cells demonstrate remarkable remission rates in pediatric and adult patients with refractory or relapsed (r/r) acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). In 2016, we initiated a clinical trial with in-house produced CD19 CAR-T cells with a CD28 co-stimulatory domain. We analyzed, for the first time, differences in production features and phenotype between ALL and NHL patients. METHODS: Non-cryopreserved CAR-T cells were produced from patients' peripheral blood mononuclear cells within 9 to 10 days. 93 patients with r/r ALL and NHL were enrolled under the same study. CAR-T cells of ALL and NHL patients were produced simultaneously, allowing the head-to-head comparison. RESULTS: All patients were heavily pretreated. Three patients dropped out from the study due to clinical deterioration (n=2) or production failure (n=1). Cells of ALL patients (n=37) expanded significantly better and contained more CAR-T cells than of NHL patients (n=53). Young age had a positive impact on the proliferation capacity. The infusion products from ALL patients contained significantly more naïve CAR-T cells and a significantly higher expression of the chemokine receptor CXCR3. PD-1, LAG-3, TIM-3, and CD28 were equally expressed. 100% of ALL patients and 94% of NHL patients received the target dose of 1×10e6 CAR-T/kg. The overall response rate was 84% (30/36) in ALL and 62% (32/52) in NHL. We further compared CAR-T cell infusion products to tumor infiltrating lymphocytes (TIL), another common type of T cell therapy, mainly clinically effective in solid tumors. CAR-T cells contained significantly more naïve T cells and central memory T cells and significantly less CCR5 compared to TIL infusion products. CONCLUSIONS: The in-house production of CAR-T cells is highly efficient and fast. Clinical response rate is high. CAR-T cells can be successfully produced for 99% of patients in just 9 to 10 days. Cells derived from ALL patients demonstrate a higher proliferation rate and contain higher frequencies of CAR-T cells and naïve T cells than of NHL patients. In addition, understanding the differences between CAR-T and TIL infusion products, may provide an angle to develop CAR-T cells for the treatment of solid tumors in the future. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; CAR-T: NCT02772198, First posted: May 13, 2016; TIL: NCT00287131, First posted: February 6, 2006.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Leucócitos Mononucleares/imunologia , Linfoma não Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/imunologia , Adolescente , Adulto , Fatores Etários , Antígenos CD19/genética , Antígenos CD19/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento , Adulto Jovem
10.
Bull Cancer ; 107(2): 234-243, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32035651

RESUMO

The approval of tisagenlecleucel in B-lineage acute lymphoblastic leukemias in 2017 in the USA and in 2018 in Europe not only opened new hopes but forced to rethink the hospital organizations around this innovation. Indeed, if these treatments are very effective in the short term, the complex logistics required imply high quality inter-center and intra-center collaboration. Hematology, intensive care unit, apheresis, neurology, cell therapy and biology laboratories, and radiology services must therefore act in a coordinated manner. A specialized monitoring for the mid and long term must also be implemented. Many questions remain concerning the profile of eligible patients, the short and long-term safety, the longer-term efficacy, improving the persistence of CAR-T cells, controlling the risk of tumor escape, the use of allogenic CAR-T cells, or the application of this concept to T-cell ALL. The precise evaluation of the involved costs and the cost-effectiveness of these therapies will also be the subject of future studies.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prognóstico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Recidiva , Linfócitos T/efeitos dos fármacos
11.
Cytotherapy ; 22(2): 57-69, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014447

RESUMO

Thirty years after initial publications of the concept of a chimeric antigen receptor (CAR), the U.S. Food and Drug Administration (FDA) approved the first anti-CD19 CAR T-cell therapy. Unlike other immunotherapies, such as immune checkpoint inhibitors and bispecific antibodies, CAR T cells are unique as they are "living drugs," that is, gene-edited killer cells that can recognize and kill cancer. During these 30 years of development, the CAR construct, T-cell manufacturing process, and clinical patient management have gone through rounds of failures and successes that drove continuous improvement. Tisagenlecleucel was the first gene therapy to receive approval from the FDA for any indication. The initial approval was for relapsed or refractory (r/r) pediatric and young-adult B-cell acute lymphoblastic leukemia in August 2017 and in May 2018 for adult r/r diffuse large B-cell lymphoma. Here we review the preclinical and clinical development of what began as CART19 at the University of Pennsylvania and later developed into tisagenlecleucel.


Assuntos
Antígenos CD19/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Adulto , Anticorpos Biespecíficos , Contagem de Células , Terapia Baseada em Transplante de Células e Tecidos/métodos , Engenharia Genética , Terapia Genética/métodos , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva , Linfoma de Células B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos Quiméricos/genética , Estados Unidos , United States Food and Drug Administration
14.
Environ Res ; 182: 109023, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911233

RESUMO

BACKGROUND: Although epidemiologic studies suggest that early immune stimulation is protective against childhood leukemia, evidence for this relationship is equivocal for Hispanic children, who are disproportionately affected by this disease. The complex biological processes underlying immune stimulation and leukemogenesis may benefit from novel statistical approaches that account for mixed exposures and their nonlinear interactions. In this study, we utilized targeted machine learning and traditional statistical methods to investigate the association of multiple measures of early immune stimulation with acute lymphoblastic leukemia (ALL) in Costa Rican children. MATERIALS AND METHODS: We used data from a population-based case-control study conducted in Costa Rica (2001-2003). Cases of ALL (n = 240) were diagnosed in 1995-2000 (age >1 year and <15 years at diagnosis) and were identified through the National Cancer Registry and National Children's Hospital. Population controls (n = 578) were frequency-matched to cases by birth year and drawn from the National Birth Registry. Data on surrogate measures of early immune stimulation were collected through in-home interviews. We fitted multivariable models, utilizing targeted causal inference (varimpact), unconditional logistic regression, and latent class analysis (LCA). RESULTS: In varimpact analysis, contact with any pet [risk difference (RD) = -0.17, 95% CI: -0.25, -0.10)] or any farm animal (RD = -0.07, 95% CI: -0.13, 0.00) and allergies (RD = -0.08, 95% CI: -0.17, 0.01) were associated with a reduced risk of ALL, whereas experiencing a fever longer than one week was associated with an increased risk (RD = 0.23, 95% CI: 0.12, 0.33). In unconditional logistic regression models, contact with any pet or farm animal and a complete vaccination scheme were inversely associated with odds of ALL (OR = 0.44, 95% CI: 0.31, 0.62; OR = 0.66, 95% CI: 0.49, 0.90; OR = 0.45, 95% CI: 0.24, 0.83; respectively), whereas experiencing a fever longer than one week was positively associated with ALL (OR = 2.44, 95% CI: 1.61, 3.70). Two-class and three-class LCA revealed a group with elevated risk for ALL whose exposure profile was mainly characterized by reduced exposure to pets and farm animals. CONCLUSIONS: Using distinct statistical approaches, we observed that exposure to pets and farm animals was inversely associated with ALL risk, whereas having a fever longer than one week (a putative proxy of severe infection) was associated with an increased risk. For multifactorial diseases such as childhood leukemia, we recommend estimating the joint effects of multiple exposures by applying diverse statistical methods and interpreting their results together. Overall, we found support for the hypothesis that early immune stimulation offers protection against childhood ALL.


Assuntos
Animais Domésticos , Animais de Estimação , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Estudos de Casos e Controles , Criança , Costa Rica , Humanos , Lactente , Modelos Logísticos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Fatores de Risco
15.
Int J Hematol ; 111(5): 719-723, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31894532

RESUMO

It is well known that the second-generation tyrosine kinase inhibitor dasatinib evokes an immunological reaction as an off-target effect and induces large granular lymphocytes (LGLs) expansion in 30% of patients. However, LGLs expansion in nilotinib-treated patients is rare. We report the case of a 65-year-old patient with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) who showed LGLs expansion during nilotinib treatment. The patient achieved complete remission (CR) after multi-agent chemotherapy combined with dasatinib treatment. However, ALL relapsed in the central nervous system and bone marrow when treatment was interrupted due to interstitial pneumonia. Nilotinib treatment was subsequently started and the patient achieved second CR. Marked peripheral blood lymphocytosis emerged after the start of nilotinib treatment. CD8 + CD57 + cytotoxic T cells were predominantly expanded and showed strong cytocidal activity against K562 Ph-positive leukemia cells. These results suggest that similar to dasatinib, nilotinib can induce LGLs expansion, possibly contributing to long-term remission in patients with Ph-ALL.


Assuntos
Linfócitos/imunologia , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Pirimidinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD57 , Linfócitos T CD8-Positivos/imunologia , Dasatinibe , Humanos , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
17.
Pediatr Blood Cancer ; 67(1): e28021, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31571395

RESUMO

Hypersensitivity to pegaspargase is associated with inferior survival in pediatric patients with acute lymphoblastic leukemia and lymphoblastic lymphoma. In the past year, drug-supply shortages have led to the lack of an available alternative to pegaspargase. Rather than omit asparaginase from the treatment of acute lymphoblastic leukemia or lymphoblastic lymphoma patients with hypersensitivity to pegaspargase, we continued pegaspargase treatments for nine pediatric patients, utilizing a rapid desensitization protocol. There were no adverse events related to the pegaspargase during desensitization, and all patients who were checked had asparaginase serum levels above the threshold of 0.1 IU/mL at 7 to 14 days after pegaspargase therapy.


Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/uso terapêutico , Dessensibilização Imunológica/métodos , Linfoma de Células T/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Humanos , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico
18.
Acta Haematol ; 143(2): 112-117, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31288222

RESUMO

In addition to intrinsic factors, leukemia cell growth is influenced by the surrounding nonhematopoietic cells in the leukemic microenvironment, including fibroblasts, mesenchymal stem cells, vascular cells, and various immune cells. Despite the fact that macrophages are an important component of human innate immunity, tumor-associated macrophages (TAMs) have long been considered as an accomplice promoting tumor growth and metastasis. TAMs are activated by an abnormal malignant microenvironment, polarizing into a specific phenotype and participating in tumor progression. TAMs that exist in the microenvironment of different types of leukemia are called leukemia-associated macrophages (LAMs), which are reported to be associated with the progression of leukemia. This review describes the role of LAMs in different leukemia subtypes.


Assuntos
Leucemia/patologia , Macrófagos/metabolismo , Progressão da Doença , Humanos , Imunidade Inata , Leucemia/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Macrófagos/citologia , Macrófagos/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Microambiente Tumoral
19.
Life Sci ; 242: 117223, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881222

RESUMO

Acute lymphoblastic leukemia (ALL) is an aggressive cancer in children and adults which possess higher CD47 expression than normal cells. ALL chemotherapy has a lot of side effects and in most cases is ineffective. However arrival of Natural killer (NK) cell immunotherapy raised hopes for successful treatment of cancers, tailoring NK cells to meet clinical requirements is still under investigation. Of note, CD16+ (FCγIIIa) NK cells eliminate tumor cells with antibody dependent cell cytotoxicity (ADCC) mechanism. Therefore, we evaluated ADCC effect of cord blood stem cell derived CD16+ NK cells with using anti CD47 blocking antibody. CD16+ NK cells generated efficiently from CD34 positive cord blood cells in vitro using IL-2, IL-15 and IL-21 cytokines, although it was not dose dependent. CD16+ cells derived from CD34+ cells in day 14 of culture efficiently increased apoptosis in ALL cells, produced INFγ and increased CD107-a expression when used anti CD47 antibody (increased around 30-40%). Interestingly, CD16+ NK cell cytotoxicity slightly increased in combination with macrophages against ALL cells (around 10%). Taken together, our findings induced this hope that cord blood stem cell derived CD16+ NK cells exploit antitumor immune response in cancer therapy with using anti-CD47 antibody.


Assuntos
Anticorpos Anti-Idiotípicos/uso terapêutico , Antígeno CD47/imunologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Células Matadoras Naturais/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de IgG/imunologia , Anticorpos Anti-Idiotípicos/imunologia , Western Blotting , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Imunoterapia/métodos , Microscopia de Fluorescência , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia
20.
Blood ; 135(9): 597-609, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-31830245

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy has proven effective in relapsed and refractory B-cell malignancies, but resistance and relapses still occur. Better understanding of mechanisms influencing CAR T-cell cytotoxicity and the potential for modulation using small-molecule drugs could improve current immunotherapies. Here, we systematically investigated druggable mechanisms of CAR T-cell cytotoxicity using >500 small-molecule drugs and genome-scale CRISPR-Cas9 loss-of-function screens. We identified several tyrosine kinase inhibitors that inhibit CAR T-cell cytotoxicity by impairing T-cell signaling transcriptional activity. In contrast, the apoptotic modulator drugs SMAC mimetics sensitized B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma cells to anti-CD19 CAR T cells. CRISPR screens identified death receptor signaling through FADD and TNFRSF10B (TRAIL-R2) as a key mediator of CAR T-cell cytotoxicity and elucidated the RIPK1-dependent mechanism of sensitization by SMAC mimetics. Death receptor expression varied across genetic subtypes of B-cell malignancies, suggesting a link between mechanisms of CAR T-cell cytotoxicity and cancer genetics. These results implicate death receptor signaling as an important mediator of cancer cell sensitivity to CAR T-cell cytotoxicity, with potential for pharmacological targeting to enhance cancer immunotherapy. The screening data provide a resource of immunomodulatory properties of cancer drugs and genetic mechanisms influencing CAR T-cell cytotoxicity.


Assuntos
Citotoxicidade Imunológica/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Citotóxicos/imunologia , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Testes Imunológicos de Citotoxicidade/métodos , Humanos , Ativação Linfocitária/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Receptores de Antígenos Quiméricos
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