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1.
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
2.
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
3.
Cancer Metastasis Rev ; 38(4): 595-610, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31811553

RESUMO

The 5-year survival rate for children and adolescents with acute lymphoblastic leukemia (ALL) has improved to more than 90% in high-income countries. However, further increases in the intensity of conventional chemotherapy would be associated with significant adverse effects; therefore, novel approaches are necessary. The last decade has seen significant advances in targeted therapy with immunotherapy and molecular therapeutics, as well as advances in risk stratification for therapy based on somatic and germline genetic analysis and monitoring of minimal residual disease. For immunotherapy, the approval of antibody-based therapy (with blinatumomab in 2014 and inotuzumab ozogamicin in 2017) and T cell-based therapy (with tisagenlecleucel in 2017) by the US Food and Drug Administration has significantly improved the response rate and outcomes in patients with relapsed/refractory B-ALL. These strategies have also been tested in the frontline setting, and immunotherapy against a new ALL-associated antigen has been developed. Incorporating effective immunotherapy into ALL therapy would enable the intensity of conventional chemotherapy to be decreased and thereby reduce associated toxicity, leading to further improvement in survival and quality of life for patients with ALL.


Assuntos
Imunoterapia/métodos , Pediatria/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Antineoplásicos Imunológicos/uso terapêutico , Criança , Ensaios Clínicos Fase III como Assunto , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Nat Med ; 25(9): 1408-1414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477906

RESUMO

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.


Assuntos
Antígenos CD19/administração & dosagem , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Antígenos CD19/genética , Antígenos CD19/imunologia , Criança , Pré-Escolar , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
6.
Hematol Oncol ; 37(5): 601-608, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31465532

RESUMO

Ninety percent of relapse/refractory B-cell acute lymphatic leukemia (R/R B-ALL) patients can achieve complete remission (CR) after CD19-targeting chimeric antigen receptor T (CAR-T) cell therapy. However, around 50% of them relapse in 1 year. Persistent CAR-T cell engraftment is considered as the key to remain durable remission. Here, we initiated a phase I study to treat 10 pediatric B-ALL patients using a CD19-targeted second generation CAR with a 4-1BB intracellular costimulatory domain. All patients received a standard fludarabine and cyclophosphamide (FC) preconditioning regiment, followed by a CAR-T infusion with a median number of 0.5 (0.3-1.58) × 106 CAR+ T cells/kg. The pretreatment tumor burdens were high with a median bone marrow (BM) blasts percentage of 59.2% (7.31%-86.2%), excluding one patient only with brain infiltration of leukemia cells (0% BM blasts). The initial CR rate was 80% (n = 8/10). Four patients (40%) experienced serious (grade > 2) cytokine release syndrome (CRS) and three patients (30%) with obvious neurotoxicity. Monthly assessments of CD19+ minimal residual disease (MRD) and CAR-T engraftment demonstrated the anti-CD19 activity of long-term engrafted CAR-T cell clones in one patient for more than 2 years.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prognóstico , Receptores de Antígenos de Linfócitos T/genética , Recidiva , Resultado do Tratamento
7.
Pediatr Hematol Oncol ; 36(5): 277-286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31296092

RESUMO

Asparaginase is an important component of multi-agent chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy). Hypersensitivity to the PEGylated form, pegaspargase, is the most common toxicity observed and is ideally addressed by substituting multiple doses of erwinia asparaginase for each subsequent dose of pegaspargase. An international shortage of erwinia asparaginase has limited the therapeutic options for those experiencing pegaspargase hypersensitivity. Here, we report pegaspargase can be safely administered, while maintaining sustained levels of asparaginase activity, to patients who have had a prior hypersensitivity reaction to pegaspargase by using a standard rapid desensitization protocol. Ten patients with prior hypersensitivity reactions to pegaspargase were treated by using a standardized rapid desensitization protocol. Eight patients had therapeutic asparaginase levels between days 4 and 7 of ≥0.05 IU/mL, and seven patients continued to have sustained levels above ≥0.1 IU/mL between days 10 and 14. Based on chemotherapy regimens, five of these patients successfully received more than one dose of pegaspargase utilizing this protocol.


Assuntos
Asparaginase , Proteínas de Bactérias , Dessensibilização Imunológica , Hipersensibilidade a Drogas/prevenção & controle , Polietilenoglicóis , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Asparaginase/imunologia , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/efeitos adversos , Proteínas de Bactérias/imunologia , Criança , Pré-Escolar , Hipersensibilidade a Drogas/imunologia , Escherichia coli/enzimologia , Feminino , Humanos , Masculino , Pectobacterium chrysanthemi/enzimologia , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
9.
Genomics Proteomics Bioinformatics ; 17(2): 190-200, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31201998

RESUMO

Chimeric antigen receptor (CAR) T cell therapy has exhibited dramatic anti-tumor efficacy in clinical trials. In this study, we reported the transcriptome profiles of bone marrow cells in four B cell acute lymphoblastic leukemia (B-ALL) patients before and after CD19-specific CAR-T therapy. CD19-CAR-T therapy remarkably reduced the number of leukemia cells, and three patients achieved bone marrow remission (minimal residual disease negative). The efficacy of CD19-CAR-T therapy on B-ALL was positively correlated with the abundance of CAR and immune cell subpopulations, e.g., CD8+ T cells and natural killer (NK) cells, in the bone marrow. Additionally, CD19-CAR-T therapy mainly influenced the expression of genes linked to cell cycle and immune response pathways, including the NK cell mediated cytotoxicity and NOD-like receptor signaling pathways. The regulatory network analyses revealed that microRNAs (e.g., miR-148a-3p and miR-375), acting as oncogenes or tumor suppressors, could regulate the crosstalk between the genes encoding transcription factors (TFs; e.g., JUN and FOS) and histones (e.g., HIST1H4A and HIST2H4A) involved in CD19-CAR-T therapy. Furthermore, many long non-coding RNAs showed a high degree of co-expression with TFs or histones (e.g., FOS and HIST1H4B) and were associated with immune processes. These transcriptome analyses provided important clues for further understanding the gene expression and related mechanisms underlying the efficacy of CAR-T immunotherapy.


Assuntos
Antígenos CD19/metabolismo , Redes Reguladoras de Genes , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transcriptoma/genética , Adulto , Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores de Antígenos de Linfócitos T , Fatores de Transcrição/metabolismo
10.
Int J Exp Pathol ; 100(3): 184-191, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31090156

RESUMO

The expression of microRNA in eukaryotic cells is subject to tightly regulated processing. The altered expression of microRNAs in a number of cancers suggests their contribution to disease pathogenesis, where processing pathways may be involved in disease pathogenesis. In the present study, we evaluated changes in the profile of two main components of microRNA biogenesis, AGO2 and DICER, and assessed their correlation with disease progression in childhood acute lymphoblastic leukaemia (ALL). To achieve this aim, 25 patients afflicted with ALL were included in the study along with 25 healthy subjects as control. The expression level of AGO2 and DICER was evaluated by real-time PCR. The results revealed an increase in the expression of DICER and a decrease in AGO2 in patients. The correlation between the alteration levels of these genes with pathologic events was also studied. This increase or decrease proved to be directly correlated with the progression of the disease particularly in L1 to L2. According to the obtained results, it can be deduced that dysregulation in transcription of DICER and AGO2, involved in the formation of mature microRNAs in cytoplasm of ALL cancer cells, is a part of the pathological molecular mechanism implicated in the exacerbation of this malignancy. Therefore, the genes involved in microRNAs biogenesis that have been studied here could be considered as candidate prognostic markers especially in childhood ALL which will help towards a better understanding of the molecular basis of ALL.


Assuntos
Proteínas Argonauta/metabolismo , Linfócitos B/citologia , Linhagem da Célula/imunologia , RNA Helicases DEAD-box/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Ribonuclease III/metabolismo , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos
11.
J Immunol Res ; 2019: 2816498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944830

RESUMO

Regulatory T-cells (Tregs) are a very important subtype of lymphocytes when it comes to self-control in the human immunological system. Tregs are decisive not only in the protection against destruction of own tissues by autoimmune immunocompetent cells but also in the immunological answer to developing cancers. On the other hand, Tregs could be responsible for the progression of acute and chronic leukemias. In our study, we review publications available in the PUMED database concerning acute leukemia, with a particular emphasis on child's leukemias. The percentage of regulatory T-lymphocytes in peripheral blood and bone marrow was elevated compared to those in healthy individuals and correlated with progressive disease. Regulatory T-cells taken from children diagnosed with leukemia showed a higher suppressive capability, which was confirmed by detecting elevated levels of secreted IL-10 and TGF-beta. The possibility of pharmacological intervention in the self-control of the immunological system is now under extensive investigation in many human cancers. Presumably, Treg cells could be a vital part of targeted therapies. Routine Treg determination could be used to assess the severity of disease and prognosis in children with acute lymphoblastic leukemia. This proposition results from the fact that in some studies, higher percentage of Treg cells in peripheral blood was demonstrated. However, observations confirming these facts are scarce; thus, extrapolating them to the population of children with hematological malignancies needs to be verified in additional studies.


Assuntos
Leucemia Mieloide Aguda/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/imunologia , Progressão da Doença , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Linfócitos T Reguladores/classificação , Fator de Crescimento Transformador beta/imunologia
12.
Clin Adv Hematol Oncol ; 17(3): 166-175, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30969955

RESUMO

Patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in R/R ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with R/R ALL.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
13.
Pediatr Blood Cancer ; 66(8): e27765, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31012549

RESUMO

BACKGROUND: Denintuzumab mafodotin (SGN-CD19A) is a CD19-targeting antibody-drug conjugate, comprising a monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin F. Since denintuzumab mafodotin has previously shown activity against B-cell malignancies in early-stage clinical trials, it was of interest to test it against the Pediatric Preclinical Testing Program preclinical models of CD19+ pediatric acute lymphoblastic leukemia (ALL). PROCEDURES: Denintuzumab mafodotin was evaluated against eight B-cell lineage ALL patient-derived xenografts (PDXs), representing B-cell precursor ALL, Ph-like ALL, and mixed-lineage leukemia rearranged infant ALL. Denintuzumab mafodotin was administered weekly for 3 weeks at 3 mg/kg. It was also tested in combination with an induction-type chemotherapy regimen of vincristine, dexamethasone, and l-asparaginase (VXL) against three PDXs. The relationship between cell surface and gene expression of CD19 and drug activity was also assessed. RESULTS: Denintuzumab mafodotin significantly delayed the progression of seven of eight PDXs tested and achieved objective responses in five of eight. There was no apparent subtype specificity of denintuzumab mafodotin activity. No correlations were observed between CD19 mRNA or cell surface expression and denintuzumab mafodotin activity, perhaps due to small sample size, and denintuzumab mafodotin treatment did not select for reduced CD19 expression. Combining denintuzumab mafodotin with VXL achieved therapeutic enhancement compared to either treatment alone. CONCLUSIONS: Denintuzumab mafodotin showed single-agent activity against selected B-lineage ALL PDXs, although leukemia growth was evident in most models at 28 days from treatment initiation. This level of activity for denintuzumab mafodotin is consistent with that observed in adults with ALL.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19/imunologia , Imunoconjugados/administração & dosagem , Oligopeptídeos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Animais , Antígenos CD19/metabolismo , Criança , Pré-Escolar , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Oncol Rep ; 41(6): 3455-3463, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942469

RESUMO

CD19 chimeric antigen receptor (CAR) T cell therapy has changed the outcomes of relapsed/refractory B­cell leukemia and lymphoma. However, its efficacy in patients with relapsed/refractory non­Hodgkin lymphoma (NHL) has been less impressive compared with that in patients with acute lymphoid leukemia. Furthermore, immune checkpoints have a critical role in the immune system. Several clinical trials have confirmed the dramatic effects of programmed death­1/programmed death­ligand 1 (PD­1/PD­L1) inhibitors in numerous malignancies, but the immune­associated adverse events of PD­1/PD­L1 inhibitors may occur in a number of systems. The aim of the present study was to investigate the combination of CD19 CAR­T cells with a reduced dose of PD­1 inhibitor. This method is expected to overcome the side-effects of PD­1 inhibitors, while maintaining therapeutic efficacy. The findings demonstrated that a reduced dose of PD­1 inhibitor did not affect the transfection rate, proliferation rate or cytokine secretion of CD19 CAR­T cells. An interesting finding of the present study was that the number of PD­1­positive cells CAR­T cells, measured by flow cytometry, declined when they were cultured in vitro, but returned to high levels with gradual prolongation of the co­culture time of CD19 CAR­T cells with lymphoma cells; however, there was no change in the mRNA expression of T cells and CAR­T cells during this process. This phenomenon may be one of the reasons why the curative effect of CAR­T cells on B­cell lymphoma is unsatisfactory compared with B­cell leukemia. The synergistic effect of a reduced­dose PD­1 inhibitor combined with CD19 CAR­T cells from T cells highly expressing PD­1 was confirmed in a mouse trial. Mice in the combined treatment group achieved the longest survival time. In this group, the proportion of CAR­T cells and the level of interleukin­6 were higher compared with those in the CAR­T cell group. In conclusion, a reduced dose of a PD­1 inhibitor combined with CD19 CAR­T cells appears to be a promising treatment option for relapsed/refractory B­NHL exhibiting high PD­1 expression by T cells. This method may achieve good clinical efficacy while reducing the side-effects of PD­1 inhibitors.


Assuntos
Linfoma/terapia , Nivolumabe/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Antígenos CD19/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva/métodos , Linfoma/genética , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptor de Morte Celular Programada 1/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Biologicals ; 59: 47-55, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30871932

RESUMO

Acute lymphoblastic leukemia (ALL) is a type of cancer with a high incidence in children. The enzyme l-asparaginase (ASNase) constitutes a key element in the treatment of this disease. Four formulations of ASNase from a bacterial source are currently available. However, these formulations are characterized by their high immunogenicity, resulting in the inactivation of the drug, as well as in the occurrence of hypersensitivity reactions in a large number of patients. In this work, we performed an immunoinformatic analysis in order to clarify structural aspects of the immunogenicity of the asparaginase from Escherichia coli and Erwinia carotovora. For this purpose, we performed the prediction of immunogenic and allergenic epitopes in the structure of asparaginases by using the relative frequency of immunogenic peptides for the eight alleles most frequently distributed worldwide. This study showed that there are no significant differences in the level of immunogenicity between the two enzymes, while asparaginase from E. coli presented a higher relative frequency of allergenic epitopes. These results are consistent with previously published reports. However, from a structural point of view, to the best of our knowledge, this is the first report describing the structural determinants that contribute to the hypersensitivity response to this treatment.


Assuntos
Asparaginase/imunologia , Proteínas de Bactérias/imunologia , Epitopos/imunologia , Escherichia coli/enzimologia , Pectobacterium carotovorum/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Sequência de Aminoácidos , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Proteínas de Bactérias/química , Proteínas de Bactérias/uso terapêutico , Criança , Simulação por Computador , Epitopos/química , Escherichia coli/genética , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/imunologia , Pectobacterium carotovorum/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Conformação Proteica , Homologia de Sequência de Aminoácidos , Especificidade da Espécie
16.
Nat Rev Clin Oncol ; 16(6): 372-385, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30837712

RESUMO

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.


Assuntos
Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Antígenos CD19/imunologia , Ensaios Clínicos como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Células B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prevenção Secundária
17.
Pharmacol Rep ; 71(2): 311-318, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30826572

RESUMO

BACKGROUND: L-asparaginase (L-asp) remains one of the key components of acute lymphoblastic leukemia therapy. Immune reactions to the drug are associated with its diminished activity. The aim of the study was to determine the level of IgM, IgG and IgE-class anti-L-asp antibodies during the induction and reinduction phases of acute lymphoblastic leukemia therapy and their influence on L-asp activity. METHODS: The study group comprised 65 patients treated for acute lymphoblastic leukemia in one pediatric oncology center. L-asp antibodies were assessed using ELISA at the end of the induction and reinduction phases. L-asp activity was assessed prior to each drug administration by colorimetry. RESULTS: At the end of the first exposure to L-asp antibodies were detected in 35 patients (54%). In the reinduction phase of the treatment anti-L-asp antibodies were found in 38/55 patients (69%). In the induction phase patients with inadequate L-asp activity had higher IgM concentrations (median 5.88 versus 2.81 µg/mL, p = 0.03). In the reinduction phase IgG and IgM levels correlated inversely with L-asp activity. Patients with L-asp allergy had higher levels of IgG (median 61.6 versus 18.36 µg/mL, p = 0.01), whereas higher IgE levels were noted in the group of patients with inadequate drug activity (median 0.91 versus 0.64 µg/mL, p = 0.03). CONCLUSIONS: Subsequent exposure to L-asp in the treatment of acute lymphoblastic leukemia was associated with the increase of anti-L-asp antibodies in all studied classes. However, the changes observed in specific classes of antibodies were not distinctive for L-asp hypersensitivity or inactivation, suggesting that the mechanism is more complex.


Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Imunoglobulina G/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Anticorpos , Antineoplásicos/imunologia , Asparaginase/imunologia , Criança , Pré-Escolar , Colorimetria , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina E/imunologia , Imunoglobulina M/imunologia , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia
18.
Hum Immunol ; 80(6): 400-408, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30716352

RESUMO

Advances in multi-agent chemotherapy and supportive care have dramatically improved survival of children with B-cell acute lymphoblastic leukemia (B-ALL); however, patients with relapsed and refractory disease continue to represent a therapeutic challenge. Hematopoietic stem cell transplant was the first immunotherapeutic approach to be used in the treatment of patients with relapsed or refractory disease. However, novel therapies such as bispecific antibodies that engage T-cells and chimeric antigen receptor T-cells (CAR-T) therapy have emerged as novel FDA-approved options that have the potential to become the new standard of care for these difficult-to-treat leukemias. With multiple immunotherapeutic agents in the drug development pipeline, it is important for cancer researchers and oncologists to be familiar with these agents, including their mechanism of action, side effects and efficacy. In this paper, we review the role of the human immune system in the development and treatment of childhood ALL and provide an overview of current and upcoming immunotherapeutic treatment approaches.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Imunoterapia Adotiva , Imunoterapia/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/imunologia , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia
19.
Ann Lab Med ; 39(4): 358-366, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30809981

RESUMO

BACKGROUND: JL1 is a newly identified CD43 epitope that specifically recognizes leukemic cells. We analyzed the incidence of JL1 expression and compared the clinical, immunophenotypic, and genetic characteristics of de novo pediatric acute leukemia patients with respect to JL1 expression status to determine the therapeutic potential of an anti-JL1 antibody. METHODS: Seventy-eight patients with pediatric acute leukemia (52 with ALL, 26 with AML) diagnosed between December 2014 and January 2016 were enrolled prospectively. Flow cytometry for JL1 expression was performed at diagnosis. Clinical, immunophenotypic, and genetic characteristics were compared with respect to JL1 expression status by the Student t-test/Mann-Whitney U test and chi-square test/Fisher's exact test. RESULTS: The incidence of JL1 expression was 76.9% and 84.6% in ALL and AML patients, respectively. ALL patients with JL1 expression showed higher CD10 and cytoplasmic IgM expressions than those without JL1 expression (P=0.022 and 0.003, respectively) and were associated with TCF3-PBX1 and KMT2A-MLLT1 translocations. AML patients with JL1 expression showed higher CD13 and lower CD65 and CD15 expressions than those without JL1 expression (P=0.013, 0.007, and 0.024, respectively) and were associated with RUNX1-RUNX1T1, PML-RARA, and CBFB-MYH11 translocations. The JL1 expression incidence did not differ between ALL and AML, and the JL1 expression status did not affect prognosis. CONCLUSIONS: Our findings support the potential therapeutic role of anti-JL1 monoclonal antibodies; JL1 expression was associated with specific immunophenotypes and genetic abnormalities. Future studies should examine the prognostic impact of JL1 expression in pediatric acute leukemias.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Anticorpos Monoclonais/uso terapêutico , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Imunofenotipagem , Lactente , Cariótipo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Leucossialina/química , Leucossialina/metabolismo , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prognóstico , Estudos Prospectivos , Proteína 1 Parceira de Translocação de RUNX1/genética , Estatísticas não Paramétricas
20.
Leukemia ; 33(7): 1570-1582, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30635636

RESUMO

As novel immunological treatments are gaining a foothold in the treatment of acute lymphoblastic leukemia (ALL), it is elemental to examine ALL immunobiology in more detail. We used multiplexed immunohistochemistry (mIHC) to study the immune contexture in adult precursor B cell ALL bone marrow (BM). In addition, we developed a multivariate risk prediction model that stratified a poor survival group based on clinical parameters and mIHC data. We analyzed BM biopsy samples of ALL patients (n = 52) and healthy controls (n = 14) using mIHC with 30 different immunophenotype markers and computerized image analysis. In ALL BM, the proportions of M1-like macrophages, granzyme B+CD57+CD8+ T cells, and CD27+ T cells were decreased, whereas the proportions of myeloid-derived suppressor cells and M2-like macrophages were increased. Also, the expression of checkpoint molecules PD1 and CTLA4 was elevated. In the multivariate model, age, platelet count, and the proportion of PD1+TIM3+ double-positive CD4+ T cells differentiated a poor survival group. These results were validated by flow cytometry in a separate cohort (n = 31). In conclusion, the immune cell contexture in ALL BM differs from healthy controls. CD4+PD1+TIM3+ T cells were independent predictors of poor outcome in our multivariate risk model, suggesting that PD1 might serve as an attractive immuno-oncological target in B-ALL.


Assuntos
Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Microambiente Tumoral/imunologia , Adolescente , Adulto , Idoso , Antígeno CTLA-4 , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
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