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1.
Blood ; 140(4): 335-348, 2022 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-35275990

RESUMEN

Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T-cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T cells is predictive of relapse and poor overall survival in B-cell acute lymphoblastic leukemia (B-ALL). Thus, therapies that counter T-cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti-PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. Single-cell RNA-sequence analysis revealed that B-ALL induces a unique subset of CD4+ T cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PD-L1 dramatically improves long-term survival of leukemic mice. Depletion of CD4+ T cells prior to therapy completely abrogates the survival benefit, implicating CD4+ T cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PD-L1 leads to clonal expansion of leukemia-specific CD4+ T cells with the aforementioned helper/cytotoxic phenotype as well as reduced expression of exhaustion markers. These findings support efforts to use PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.


Asunto(s)
Antineoplásicos , Leucemia de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animales , Antígeno B7-H1 , Linfocitos T CD4-Positivos , Humanos , Ratones , Pirimidinas , Recurrencia
2.
Am J Hematol ; 94(6): 658-666, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30916801

RESUMEN

Indolent B-cell lymphomas other than follicular lymphoma account for up to 10% of all B-cell neoplasms. While they typically follow a slowly progressive course, some patients experience rapid progression and early mortality. Prognostic scoring systems have not been adopted, hindering the ability of clinicians or researchers to predict outcomes, or risk-stratify patients during clinical trials. To address this, we evaluated the utility of existing prognostic indices and novel, early disease-related outcomes, to predict subsequent long term survival. Baseline characteristics and outcomes data were generated from a longitudinal cohort study that prospectively enrolled 632 patients newly diagnosed with marginal zone lymphoma, lymphoplasmacytic lymphomas, or B-cell lymphomas not otherwise specified, beginning in 2002. The International Prognostic Index (IPI), Follicular Lymphoma International Prognostic Index (FLIPI), and MALT International prognostic index (MALT-IPI) demonstrated c-statistics that ranged from 0.593-0.612 for event-free survival (EFS), and 0.683-0.714 for overall survival (OS). Patients who attained event-free survival at 12 months (EFS12) experienced similar mortality to the US general population (standardized mortality ratio [SMR] 1.19; 95% CI 0.95-1.46). Patients who did not attain EFS12 had subsequent worse morality (SMR 3.14 (95% CI 2.05-4.59). The MALT-IPI demonstrated utility in predicting subsequent long-term outcomes among patients with non-follicular indolent B-cell lymphomas. This index should be used by clinicians giving guidance to patients at the time of initial diagnosis, and risk stratification during clinical studies. The divergent long-term outcomes experienced by patients who do or do not attain EFS12 suggest there exists a subset of patients who harbor high-risk disease. Future research efforts should focus on methods to identify these patients at the time of diagnosis, in order to enable risk-tailored therapy.


Asunto(s)
Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo , Tasa de Supervivencia
3.
Haematologica ; 103(2): 297-303, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29170255

RESUMEN

The prevalence, presenting clinical and pathological characteristics, and outcomes for patients with diffuse large B-cell lymphoma that is Epstein-Barr virus positive remain uncertain as does the impact of congenital or iatrogenic immunosuppression. Patients with newly diagnosed diffuse large B-cell lymphoma with available tissue arrays were identified from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource. Patients infected with human immunodeficiency virus or who had undergone a prior organ transplant were excluded. Epstein-Barr virus-associated ribonucleic acid testing was performed on all tissue arrays. A history of significant congenital or iatrogenic immunosuppression was determined for all patients. At enrollment, 16 of the 362 (4.4%) biopsies were positive for Epstein-Barr virus. Thirty-nine (10.8%) patients had a significant history of immunosuppression. Patients with Epstein-Barr-positive diffuse large B-cell lymphoma had no unique clinical characteristics but on pathology exhibited a higher frequency of CD30 positivity (25.0% versus 8.1%, respectively; P<0.01), and non-germinal-center subtype (62.5% versus 34.1%, respectively; P<0.01). No baseline clinical characteristics were associated with a history of immunosuppression. With a median follow up of 59 months, and after adjustment for International Prognostic Index, there was no association of Epstein-Barr virus positivity or immunosuppression with event-free survival at 24 months (odds ratio=0.49; 95% confidence interval: 0.13-1.84 and odds ratio=0.81; 95% confidence interval: 0.37-1.77) or overall survival (hazard ratio=0.86; 95% confidence interval: 0.38-1.97 and hazard ratio=1.00; 95% confidence interval: 0.57-1.74). In contrast to non-Western populations, our North American population had a low prevalence of Epstein-Barr virus-positive diffuse large B-cell lymphoma that did not convey an adverse prognosis. A history of immunosuppression, while known to be a risk factor for the development of diffuse large B-cell lymphoma, did not affect subsequent prognosis.


Asunto(s)
Terapia de Inmunosupresión/mortalidad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/virología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Herpesvirus Humano 4 , Humanos , Terapia de Inmunosupresión/métodos , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Estados Unidos , Adulto Joven
5.
Blood Adv ; 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39093952

RESUMEN

The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.

6.
J Virol ; 86(22): 12330-40, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22951828

RESUMEN

Epstein-Barr virus infection has been epidemiologically associated with the development of multiple autoimmune diseases, particularly systemic lupus erythematosus and multiple sclerosis. Currently, there is no known mechanism that can account for these associations. The germinal-center (GC) model of EBV infection and persistence proposes that EBV gains access to the memory B cell compartment via GC reactions by driving infected cells to differentiate using the virus-encoded LMP1 and LMP2a proteins, which act as functional homologues of CD40 and the B cell receptor, respectively. The ability of LMP2a, when expressed in mice, to allow escape of autoreactive B cells suggests that it could perform a similar role in infected GC B cells, permitting the survival of potentially pathogenic autoreactive B cells. To test this hypothesis, we cloned and expressed antibodies from EBV(+) and EBV(-) memory B cells present during acute infection and profiled their self- and polyreactivity. We find that EBV does persist within self- and polyreactive B cells but find no evidence that it favors the survival of pathogenic autoreactive B cells. On the contrary, EBV(+) memory B cells express lower levels of self-reactive and especially polyreactive antibodies than their uninfected counterparts do. Our work suggests that EBV has only a modest effect on the GC process, which allows it to access and persist within a subtly unique niche of the memory compartment characterized by relatively low levels of self- and polyreactivity. We suggest that this might reflect an active process where EBV and its human host have coevolved so as to minimize the virus's potential to contribute to autoimmune disease.


Asunto(s)
Linfocitos B/virología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/metabolismo , Memoria Inmunológica , Anticuerpos/química , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/virología , ADN Complementario/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Vectores Genéticos , Células HEK293 , Humanos , Leucocitos Mononucleares/virología , Riesgo , Análisis de Secuencia de ADN , Proteínas de la Matriz Viral/metabolismo
7.
Front Immunol ; 14: 1233261, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37654482

RESUMEN

CD4 T cells were initially described as helper cells that promote either the cellular immune response (Th1 cells) or the humoral immune response (Th2 cells). Since then, a plethora of functionally distinct helper and regulatory CD4 T cell subsets have been described. CD4 T cells with cytotoxic function were first described in the setting of viral infections and autoimmunity, and more recently in cancer and gut dysbiosis. Regulatory CD4 T cell subsets such as Tregs and T-regulatory type 1 (Tr1) cells have also been shown to have cytotoxic potential. Indeed, Tr1 cells have been shown to be important for maintenance of stem cell niches in the bone marrow and the gut. This review will provide an overview of cytotoxic CD4 T cell development, and discuss the role of inflammatory and Tr1-like cytotoxic CD4 T cells in maintenance of intestinal stem cells and in anti-cancer immune responses.

8.
Front Cell Dev Biol ; 9: 715901, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34631704

RESUMEN

The concept that a subset of T cells exists that specifically suppresses immune responses was originally proposed over 50 years ago. It then took the next 30 years to solidify the concept of regulatory T cells (Tregs) into the paradigm we understand today - namely a subset of CD4+ FOXP3+ T-cells that are critical for controlling immune responses to self and commensal or environmental antigens that also play key roles in promoting tissue homeostasis and repair. Expression of the transcription factor FOXP3 is a defining feature of Tregs, while the cytokine IL2 is necessary for robust Treg development and function. While our initial conception of Tregs was as a monomorphic lineage required to suppress all types of immune responses, recent work has demonstrated extensive phenotypic and functional diversity within the Treg population. In this review we address the ontogeny, phenotype, and function of the large number of distinct effector Treg subsets that have been defined over the last 15 years.

9.
BMJ Case Rep ; 20162016 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-27207984

RESUMEN

A 59-year-old man was admitted with a 3-month history of daily fevers as well as bilateral knee pain and swelling. Medical history was significant for bilateral knee arthroplasties 4 years prior to admission. Two sets of peripheral blood cultures as well as bilateral knee synovial fluid grew Enterococcus faecalis within 10 hours. Transoesophageal echocardiography revealed aortic and mitral valve vegetations suggestive of infectious endocarditis, with severe regurgitation secondary to large size. The patient's hospitalisation was complicated by acute heart failure, necessitating emergent mitral valve repair and aortic valve replacement, followed shortly thereafter by bilateral total knee arthroplasty resection with placement of antibiotic spacers. He was treated with intravenous penicillin and gentamicin for 4 months and recovered fully. He underwent repeat bilateral knee arthroplasties and was placed on amoxicillin for 6 months postoperatively, with no further evidence of infection.


Asunto(s)
Endocarditis Bacteriana/tratamiento farmacológico , Enterococcus faecalis/aislamiento & purificación , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Ecocardiografía Transesofágica , Endocarditis Bacteriana/complicaciones , Gentamicinas/administración & dosificación , Gentamicinas/uso terapéutico , Infecciones por Bacterias Grampositivas/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Penicilinas/administración & dosificación , Penicilinas/uso terapéutico , Infecciones Relacionadas con Prótesis/diagnóstico por imagen , Infecciones Relacionadas con Prótesis/microbiología , Líquido Sinovial/microbiología , Resultado del Tratamiento
10.
Curr Opin Virol ; 3(3): 227-32, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23683686

RESUMEN

Epstein-Barr virus (EBV) maintains a lifelong infection. According to the germinal center model (GCM), latently infected B cells transit the germinal center (GC) to become resting memory cells. Here, the virus resides quiescently, occasionally reactivating to infect new B cells, completing the cycle of infection. The GCM remains the only model that explains EBV biology and the pathogenesis of lymphoma. Recent work suggests modifications to the model notably that the virus contributes only modestly to the GC process and predictions from mathematical models that quiescence within memory B cells shapes the overall structure of viral infection but is not essential for persistence. Rather, it is the cycle of infection which allows viral persistence at the very low levels observed.


Asunto(s)
Infecciones por Virus de Epstein-Barr/patología , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/fisiología , Latencia del Virus , Linfocitos B/virología , Herpesvirus Humano 4/patogenicidad , Humanos
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