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1.
Exp Hematol ; 106: 3-18, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34879258

RESUMEN

T Cells comprise many subtypes of specified lymphocytes, and their differentiation and function take place in different tissues. This cellular diversity is also observed in the multiple ways T-cell transformation gives rise to a variety of T-cell neoplasms. This review covers the main types of T-cell malignancies and their specific characteristics, emphasizing recent advances at the cellular and molecular levels as well as differences and commonalities among them.


Asunto(s)
Leucemia de Células T/patología , Linfoma de Células T/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Linfocitos T/patología , Animales , Aberraciones Cromosómicas , Humanos , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Leucemia de Células T/terapia , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/terapia , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Transducción de Señal , Linfocitos T/metabolismo
2.
Blood Cancer J ; 11(6): 119, 2021 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-34162832

RESUMEN

Chimeric antigen receptor (CAR) T-cell therapy is the most active field in immuno-oncology and brings substantial benefit to patients with B cell malignancies. However, the complex procedure for CAR T-cell generation hampers its widespread applications. Here, we describe a novel approach in which human CAR T cells can be generated within the host upon injecting an Adeno-associated virus (AAV) vector carrying the CAR gene, which we call AAV delivering CAR gene therapy (ACG). Upon single infusion into a humanized NOD.Cg-Prkdcscid Il2rgem26/Nju tumor mouse model of human T-cell leukemia, AAV generates sufficient numbers of potent in vivo CAR cells, resulting in tumor regression; these in vivo-generated CAR cells produce antitumor immunological characteristics. This instantaneous generation of in vivo CAR T cells may bypass the need for patient lymphodepletion, as well as the ß processes of traditional CAR T-cell production, which may make CAR therapy simpler and less expensive. It may allow the development of intricate, individualized treatments in the form of on-demand and diverse therapies.


Asunto(s)
Dependovirus , Terapia Genética , Vectores Genéticos , Leucemia de Células T , Receptores Quiméricos de Antígenos , Transducción Genética , Animales , Células HEK293 , Humanos , Células Jurkat , Leucemia de Células T/genética , Leucemia de Células T/inmunología , Leucemia de Células T/terapia , Ratones , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Leukemia ; 35(12): 3466-3481, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34035409

RESUMEN

Targeting T cell malignancies using chimeric antigen receptor (CAR) T cells is hindered by 'T v T' fratricide against shared antigens such as CD3 and CD7. Base editing offers the possibility of seamless disruption of gene expression of problematic antigens through creation of stop codons or elimination of splice sites. We describe the generation of fratricide-resistant T cells by orderly removal of TCR/CD3 and CD7 ahead of lentiviral-mediated expression of CARs specific for CD3 or CD7. Molecular interrogation of base-edited cells confirmed elimination of chromosomal translocations detected in conventional Cas9 treated cells. Interestingly, 3CAR/7CAR co-culture resulted in 'self-enrichment' yielding populations 99.6% TCR-/CD3-/CD7-. 3CAR or 7CAR cells were able to exert specific cytotoxicity against leukaemia lines with defined CD3 and/or CD7 expression as well as primary T-ALL cells. Co-cultured 3CAR/7CAR cells exhibited highest cytotoxicity against CD3 + CD7 + T-ALL targets in vitro and an in vivo human:murine chimeric model. While APOBEC editors can reportedly exhibit guide-independent deamination of both DNA and RNA, we found no problematic 'off-target' activity or promiscuous base conversion affecting CAR antigen-specific binding regions, which may otherwise redirect T cell specificity. Combinational infusion of fratricide-resistant anti-T CAR T cells may enable enhanced molecular remission ahead of allo-HSCT for T cell malignancies.


Asunto(s)
Antígenos CD7/genética , Complejo CD3/genética , Inmunoterapia Adoptiva/métodos , Leucemia de Células T/terapia , Linfocitos T/inmunología , Animales , Antígenos CD7/química , Antígenos CD7/metabolismo , Complejo CD3/antagonistas & inhibidores , Complejo CD3/metabolismo , Sistemas CRISPR-Cas , Línea Celular Tumoral , Femenino , Edición Génica , Humanos , Leucemia de Células T/inmunología , Leucemia de Células T/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925571

RESUMEN

With recent clinical breakthroughs, immunotherapy has become the fourth pillar of cancer treatment. Particularly, immune cell-based therapies have been envisioned as a promising treatment option with curative potential for leukemia patients. Hence, an increasing number of preclinical and clinical studies focus on various approaches of immune cell-based therapy for treatment of acute leukemia (AL). However, the use of different immune cell lineages and subsets against different types of leukemia and patient disease statuses challenge the interpretation of the clinical applicability and outcome of immune cell-based therapies. This review aims to provide an overview on recent approaches using various immune cell-based therapies against acute B-, T-, and myeloid leukemias. Further, the apparent limitations observed and potential approaches to overcome these limitations are discussed.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Enfermedad Aguda , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Inmunoterapia , Inmunoterapia Adoptiva/tendencias , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Leucemia de Células T/metabolismo , Leucemia de Células T/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología
5.
Mol Cancer ; 19(1): 162, 2020 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-33218364

RESUMEN

Targeting T cell receptor ß-chain constant region 1 (TRBC1) CAR-T could specifically kill TRBC1+ T-cell malignancies. However, over-expressed CARs on anti-TRBC1 CAR transduced TRBC1+ T cells (CAR-C1) bound to autologous TRBC1, masking TRBC1 from identification by other anti-TRBC1 CAR-T, and moreover only the remaining unoccupied CARs recognized TRBC1+ cells, considerably reducing therapeutic potency of CAR-C1. In addition, co-culture of anti-TRBC1 CAR-T and TRBC1+ cells could promote exhaustion and terminal differentiation of CAR-T. These findings provide a rationale for pre-depleting TRBC1+ T cells before anti-TRBC1 CAR-T manufacturing.


Asunto(s)
Citotoxicidad Inmunológica/inmunología , Inmunoterapia Adoptiva/métodos , Leucemia de Células T/terapia , Depleción Linfocítica/métodos , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Apoptosis , Proliferación Celular , Humanos , Leucemia de Células T/inmunología , Leucemia de Células T/metabolismo , Leucemia de Células T/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores Quiméricos de Antígenos/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Intern Med ; 59(12): 1519-1524, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32536678

RESUMEN

A 53-year-old man presented with fulminant hepatitis due to de novo hepatitis B. He had been diagnosed previously with adult T-cell leukemia (ATL) and previously resolved hepatitis B virus infection. The ATL had been treated with cord blood transplantation (CBT). He developed fulminant hepatitis 18 months after CBT, 15 months after the withdrawal of immunosuppressants, and 10 months after vitreous injections of methotrexate for ATL-related retinal infiltration. The aggressive medical protocol included entecavir, prednisolone, plasma exchange, hemodialysis, and bilirubin adsorption. We herein report successful medical treatment for fulminant de novo hepatitis B in a patient considered unsuitable for liver transplantation.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Hepatitis B/complicaciones , Leucemia de Células T/terapia , Necrosis Hepática Masiva/etiología , Necrosis Hepática Masiva/terapia , Hepatitis B/terapia , Hepatitis B/virología , Humanos , Leucemia de Células T/complicaciones , Masculino , Necrosis Hepática Masiva/diagnóstico , Persona de Mediana Edad
8.
Cytotherapy ; 21(7): 769-781, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31160157

RESUMEN

Immunotherapy with chimeric antigen receptor T (CAR-T) cells has proved remarkably effective in recently published clinical trials. In this meta-analysis, we performed a systematic review in terms of the clinical response treated with CAR-T cells in acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and lymphomas patients. Thirty-eight published clinical studies including 665 patients were eligible for response rate (RR) evaluation. The overall pooled RR of CD19-CAR-T cells was 72% (95% confidence interval: 62-77%). The various clinical parameters were analyzed. RR was 81% in ALL, 68% in lymphoma and 70% in CLL. RR in patients who received interleukin (IL)-2 was 70%, whereas in those who did not receive IL-2, it was 74%. RR was 75% with lymphodepletion and 56% without lymphodepletion. RR with autologous cells was 76% and 57% with allogeneic cells. In conclusion, this meta-analysis showed a high clinical RR of CD19-CAR-T cell-based immunotherapy in patients with refractory B-cell malignancies.


Asunto(s)
Antígenos CD19/inmunología , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/inmunología , Leucemia de Células T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia de Células B/terapia , Leucemia de Células T/terapia , Linfoma/inmunología , Linfoma/terapia , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células T/inmunología , Linfoma de Células T/terapia , Masculino , Receptores Quiméricos de Antígenos/genética , Linfocitos T/metabolismo , Linfocitos T/trasplante
9.
Medicine (Baltimore) ; 98(12): e14786, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30896621

RESUMEN

RATIONALE: Granulocyte colony-stimulating factor (G-CSF) is most frequently used in healthy donors to mobilize progenitor cells into the peripheral blood for collection. While mild thrombocytopenia is common in allogeneic peripheral blood stem cell transplant donors after G-CSF mobilization, serious thrombocytopenia is rarely reported. Herein, we report a case of severe thrombocytopenia caused by G-CSF in a 14-year-old healthy donor and review the relevant literature. To our knowledge, this is the first reported case of severe thrombocytopenia caused by G-CSF in a healthy adolescent donor. PATIENT CONCERNS: A 14-year-old sister of a girl with T lymphocyte leukemia was selected as a matched donor for transplantation. The donor was healthy with normal blood parameters. DIAGNOSES: The donor received 10 µg/kg/day G-CSF via subcutaneous injection. On day 4 of G-CSF administration, blood tests before stem cell collection indicated that platelets dropped to 51 g/L. Abdominal ultrasound showed that the spleen was mildly enlarged. INTERVENTIONS: In order to prevent blood loss and other effects caused by a too low platelet count after collection, the donor's peripheral blood hematopoietic stem cells were collected after platelet transfusion. OUTCOMES: Checkups for 1 year after G-CSF administration showed normal blood parameters. LESSONS: Due to the rare risk of severe thrombocytopenia in G-CSF mobilization, it is necessary to routinely monitor blood parameters during mobilization to ensure smooth progress of the transplantation process.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/efectos adversos , Donadores Vivos , Hermanos , Trombocitopenia/inducido químicamente , Adolescente , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Leucemia de Células T/terapia , Trasplante de Células Madre de Sangre Periférica/métodos
10.
Curr Oncol Rep ; 21(5): 40, 2019 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-30919085

RESUMEN

PURPOSE OF REVIEW: Peripheral natural killer (NK) and T cell neoplasms comprise approximately 10-15% of non-Hodgkin lymphomas. There are 27 different subtypes of peripheral NK and T cell neoplasms, each of which is relatively uncommon. Treatment has been largely extrapolated from case series, retrospective reports, and paradigms developed for the aggressive B cell lymphomas. This review explores the current knowledge of the characteristics, outcome, and treatment of CNS T cell and NK neoplasms. RECENT FINDINGS: Primary and secondary CNS NK and T cell malignancies confer significant morbidity and poor prognosis. Despite clinical heterogeneity between the 27 subtypes, high-dose methotrexate-based regimens seem most effective overall. The role of prophylaxis against secondary CNS involvement remains controversial. Autologous stem cell transplant and immunotherapy are potential for promising future therapies. Current understanding of incidence, outcome, and optimal treatment strategies for CNS T cell and NK neoplasms is limited, in large part due to their diversity and rarity. Prognosis is poor, except in a few reports of long-term survival in patients most often treated with combination therapy including high-dose methotrexate. A future prospective study on treatment and outcome in CNS T cell and NK neoplasms is needed to better define these diseases.


Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/terapia , Células Asesinas Naturales/patología , Linfocitos T/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/mortalidad , Neoplasias del Sistema Nervioso Central/patología , Terapia Combinada , Humanos , Leucemia de Células T/diagnóstico , Leucemia de Células T/mortalidad , Leucemia de Células T/patología , Leucemia de Células T/terapia , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/terapia , Metotrexato/uso terapéutico , Pronóstico
11.
Clin Cancer Res ; 25(1): 222-239, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30224337

RESUMEN

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. EXPERIMENTAL DESIGN: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models. RESULTS: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. CONCLUSIONS: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.


Asunto(s)
Histona Demetilasas con Dominio de Jumonji/genética , Leucemia de Células T/genética , Receptor Notch1/genética , Peptidasa Específica de Ubiquitina 7/genética , Animales , Carcinogénesis/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Terapia Genética , Humanos , Células Jurkat , Leucemia de Células T/patología , Leucemia de Células T/terapia , Ratones , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Br J Haematol ; 180(6): 919-924, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29441563

RESUMEN

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.


Asunto(s)
Leucemia Mielomonocítica Aguda , Leucemia de Células T , Humanos , Leucemia Mielomonocítica Aguda/clasificación , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/terapia , Leucemia de Células T/clasificación , Leucemia de Células T/diagnóstico , Leucemia de Células T/genética , Leucemia de Células T/terapia , Células Mieloides , Proteínas de Neoplasias/genética , Células Precursoras de Linfocitos T
13.
Leukemia ; 32(9): 1970-1983, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29483708

RESUMEN

T cell malignancies represent a group of hematologic cancers with high rates of relapse and mortality in patients for whom no effective targeted therapies exist. The shared expression of target antigens between chimeric antigen receptor (CAR) T cells and malignant T cells has limited the development of CAR-T because of unintended CAR-T fratricide and an inability to harvest sufficient autologous T cells. Here, we describe a fratricide-resistant "off-the-shelf" CAR-T (or UCART7) that targets CD7+ T cell malignancies and, through CRISPR/Cas9 gene editing, lacks both CD7 and T cell receptor alpha chain (TRAC) expression. UCART7 demonstrates efficacy against human T cell acute lymphoblastic leukemia (T-ALL) cell lines and primary T-ALL in vitro and in vivo without the induction of xenogeneic GvHD. Fratricide-resistant, allo-tolerant "off-the-shelf" CAR-T represents a strategy for treatment of relapsed and refractory T-ALL and non-Hodgkin's T cell lymphoma without a requirement for autologous T cells.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia de Células T/inmunología , Leucemia de Células T/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Linfocitos T/inmunología , Animales , Antígenos CD7/genética , Antígenos CD7/inmunología , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Sistemas CRISPR-Cas , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Edición Génica , Orden Génico , Vectores Genéticos/genética , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia de Células T/genética , Leucemia de Células T/terapia , Masculino , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Anticuerpos de Cadena Única/genética , Anticuerpos de Cadena Única/inmunología , Anticuerpos de Cadena Única/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Nat Med ; 23(12): 1416-1423, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29131157

RESUMEN

Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor ß-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1+ and TRBC2+ compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1+, but not TRBC2+, T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Inmunoterapia Adoptiva/métodos , Leucemia de Células T/terapia , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Células Cultivadas , Células HEK293 , Humanos , Células Jurkat , Células K562 , Leucemia de Células T/inmunología , Masculino , Ratones , Terapia Molecular Dirigida/métodos , Linfocitos T/inmunología
15.
Am J Hematol ; 92(9): 892-901, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28543380

RESUMEN

With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19-directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4+ CD25+ Foxp3+ T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity. Ex vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.


Asunto(s)
Neoplasias Hematológicas , Receptores de Antígenos de Linfocitos T , Receptores CCR4/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Animales , Línea Celular Tumoral , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Humanos , Leucemia de Células T/genética , Leucemia de Células T/inmunología , Leucemia de Células T/patología , Leucemia de Células T/terapia , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores CCR4/genética , Receptores CCR4/inmunología , Linfocitos T Reguladores/patología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Blood ; 129(9): 1134-1142, 2017 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-28115371

RESUMEN

T-cell acute lymphoblastic leukemia (ALL) is a rare disease in adults with inferior survival outcomes compared with those seen in pediatric patients. Although potentially curable with ∼50% survival at 5 years, adult patients with relapsed disease have dismal outcomes with <10% of patients surviving long term. This review will discuss the diagnosis and management of adult patients with newly diagnosed T-cell ALL with an emphasis on the immunophenotypic and genetic analyses required to assign prognosis, risk stratify, and guide post-remission therapy. The evidence for the main components of complex T-cell ALL treatment regimens is described. The importance of monitoring minimal residual disease is emphasized, with a discussion of the different methods used. The results of hematopoietic cell transplantation are analyzed, and recommendations made about which patients should be considered for this intervention. The treatment of the adolescent and young adult group is delineated, and the role of using "pediatric-inspired" regimens in older adults considered. We also describe the current data and potential future options for the use of novel therapies, including nelarabine and γ-secretase inhibitors, in adult patients with T-cell ALL.


Asunto(s)
Leucemia de Células T/diagnóstico , Leucemia de Células T/terapia , Adolescente , Adulto , Femenino , Humanos , Leucemia de Células T/genética , Masculino , Adulto Joven
17.
Cell Immunol ; 313: 59-66, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28087047

RESUMEN

LMB-2, is a potent recombinant immunotoxin (RIT) that is composed of scFv antibody that targets CD25 (Tac) and a toxin fragment (PE38). It is used to treat T cell leukemias and lymphomas. To make LMB-2 less immunogenic, we introduced a large deletion in domain II and six point mutations in domain III that were previously shown to reduce T cell activation in other RITs. We found that unlike other RITs, deletion of domain II from LMB-2 severely compromised its activity. Rather than deletion, we identified T cell epitopes in domain II and used alanine substitutions to identify point mutations that diminished those epitopes. The novel RIT, LMB-142 contains a 38kDa toxin and nine point mutations that diminished T cell response to the corresponding peptides by an average of 75%. LMB-142 has good cytotoxic activity and has lower nonspecific toxicity in mice. LMB-142 should be more efficient in cancer therapy because more treatment cycles can be given.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Inmunoterapia/métodos , Inmunotoxinas/uso terapéutico , Leucemia de Células T/terapia , Pseudomonas/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/genética , Toxinas Bacterianas/genética , Línea Celular Tumoral , Proliferación Celular , Citocinas/metabolismo , Diseño de Fármacos , Ensayo de Immunospot Ligado a Enzimas , Epítopos de Linfocito T/genética , Exotoxinas/genética , Exotoxinas/uso terapéutico , Femenino , Ingeniería Genética , Humanos , Inmunotoxinas/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Leucemia de Células T/inmunología , Activación de Linfocitos , Ratones , Mutagénesis Sitio-Dirigida , Mutación/genética
18.
Nat Med ; 23(1): 18-27, 2017 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-28060797

RESUMEN

T memory stem (TSCM) cells are a rare subset of memory lymphocytes endowed with the stem cell-like ability to self-renew and the multipotent capacity to reconstitute the entire spectrum of memory and effector T cell subsets. Cumulative evidence in mice, nonhuman primates and humans indicates that TSCM cells are minimally differentiated cells at the apex of the hierarchical system of memory T lymphocytes. Here we describe emerging findings demonstrating that TSCM cells, owing to their extreme longevity and robust potential for immune reconstitution, are central players in many physiological and pathological human processes. We also discuss how TSCM cell stemness could be leveraged therapeutically to enhance the efficacy of vaccines and adoptive T cell therapies for cancer and infectious diseases or, conversely, how it could be disrupted to treat TSCM cell driven and sustained diseases, such as autoimmunity, adult T cell leukemia and HIV-1.


Asunto(s)
Autorrenovación de las Células/inmunología , Memoria Inmunológica/inmunología , Células Madre/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Diferenciación Celular , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Humanos , Leucemia de Células T/inmunología , Leucemia de Células T/terapia , Linfocitos T/trasplante
19.
Transpl Infect Dis ; 19(1)2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27860061

RESUMEN

Strongyloides stercoralis has the potential to cause accelerated autoinfection in immunocompromised hosts. Screening tests for strongyloidiasis may be falsely negative in the setting of immunosuppression. We report a case of Strongyloides hyperinfection syndrome in a patient with human T-lymphotropic virus type 1-associated T-cell leukemia early after hematopoietic stem cell transplant. The diagnosis was made by stool ova and parasite examination, despite a negative screening enzyme-linked immunosorbent assay. Because of anticipated prolonged neutropenia, an extended course of treatment was utilized.


Asunto(s)
Infecciones por HTLV-I/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Leucemia de Células T/complicaciones , Linfoma de Células T/complicaciones , Strongyloides stercoralis/aislamiento & purificación , Estrongiloidiasis/diagnóstico , Acondicionamiento Pretrasplante/efectos adversos , Adulto , Animales , Antineoplásicos/uso terapéutico , Antiprotozoarios/uso terapéutico , Ensayo de Inmunoadsorción Enzimática , Resultado Fatal , Infecciones por HTLV-I/terapia , Infecciones por HTLV-I/virología , Hepatitis B Crónica/complicaciones , Humanos , Huésped Inmunocomprometido , Leucemia de Células T/terapia , Leucemia de Células T/virología , Linfoma de Células T/terapia , Linfoma de Células T/virología , Masculino , Síndrome de Dificultad Respiratoria/complicaciones , Insuficiencia Respiratoria/etiología , Estrongiloidiasis/tratamiento farmacológico , Estrongiloidiasis/parasitología , Acondicionamiento Pretrasplante/métodos
20.
Kidney Int ; 91(3): 691-698, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27998645

RESUMEN

Thrombotic microangiopathy (TMA) is a rare disease comprising of a diverse set of disorders linked by a common histologic finding of endothelial injury. Monoclonal immunoglobulins may act as a potential trigger in the pathogenesis of TMA. To determine the prevalence of monoclonal gammopathy and clinicopathological features of TMA associated with monoclonal immunoglobulin, we performed a retrospective study in adults (18 and older) with a clinical diagnosis of TMA. Of 146 patients with TMA, we detected monoclonal immunoglobulin in 20 patients (13.7%). Among patients 50 and older, the prevalence of monoclonal gammopathy was 21%, which is approximately five-fold higher than the 4.2% expected rate in this population. Fifteen patients had monoclonal gammopathy of undetermined significance, one had multiple myeloma, one with smoldering myeloma, two had POEMS syndrome, and one had T-cell lymphocytic leukemia. Renal biopsy was performed in 15 cases, of which six showed thrombi, 11 showed mesangiolysis, and all showed double contours along glomerular capillary walls. Acute tubular injury was present in 12 cases. Treatment options were varied and included therapeutic plasma exchange in 11 patients. Ten patients progressed to end-stage renal disease, of which two received kidney transplant. Thus, our study shows an unexpectedly high prevalence of monoclonal gammopathy in patients with TMA, suggesting a potential pathogenetic mechanism. This study underscores the importance of evaluating for a monoclonal gammopathy in patients with TMA as well as the potential for targeting the underlying hematologic disorder as an approach to treating TMA.


Asunto(s)
Riñón , Leucemia de Células T/epidemiología , Mieloma Múltiple/epidemiología , Síndrome POEMS/epidemiología , Paraproteinemias/epidemiología , Microangiopatías Trombóticas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biopsia , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Inmunosupresores/uso terapéutico , Riñón/patología , Riñón/fisiopatología , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Leucemia de Células T/diagnóstico , Leucemia de Células T/terapia , Masculino , Persona de Mediana Edad , Minnesota/epidemiología , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/terapia , Síndrome POEMS/diagnóstico , Síndrome POEMS/terapia , Paraproteinemias/diagnóstico , Paraproteinemias/inmunología , Paraproteinemias/terapia , Intercambio Plasmático , Prevalencia , Diálisis Renal , Estudios Retrospectivos , Factores de Riesgo , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/terapia , Factores de Tiempo , Resultado del Tratamiento
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