RESUMEN
BACKGROUND: Secondary central nervous system lymphoma (SCNSL) confers a dismal prognosis and treatment advances are constrained by the lack of prospective studies and real-world treatment evidence. METHODS: Patients with SCNSL of all entities were included at first diagnosis and patient characteristics, treatment data, and outcomes were prospectively collected in the Secondary CNS Lymphoma Registry (SCNSL-R) (NCT05114330). FINDINGS: 279 patients from 47 institutions were enrolled from 2011 to 2022 and 243 patients (median age: 66 years; range: 23-86) were available for analysis. Of those, 49 (20 %) patients presented with synchronous (cohort I) and 194 (80 %) with metachronous SCNSL (cohort II). The predominant histology was diffuse large B-cell lymphoma (DLBCL, 68 %). Median overall survival (OS) from diagnosis of CNS involvement was 17·2 months (95 % CI 12-27·5), with longer OS in cohort I (60·6 months, 95 % CI 45·5-not estimable (NE)) than cohort II (11·4 months, 95 % CI 7·8-17·7, log-rank test p < 0.0001). Predominant induction regimens included R-CHOP/high-dose MTX (cohort I) and high-dose MTX/cytarabine (cohort II). Rituximab was used in 166 (68 %) of B-cell lymphoma. Undergoing consolidating high-dose therapy and autologous hematopoietic stem cell transplantation (HDT-ASCT) in partial response (PR) or better was associated with longer OS (HR adjusted 0·47 (95 % CI 0·25-0·89), p = 0·0197). INTERPRETATION: This study is the largest prospective cohort of SCNSL patients providing a comprehensive overview of an international real-world treatment landscape and outcomes. Prognosis was better in patients with SCNSL involvement at initial diagnosis (cohort I) and consolidating HDT-ASCT was associated with favorable outcome in patients with PR or better.
Asunto(s)
Neoplasias del Sistema Nervioso Central , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Humanos , Anciano , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Rituximab/uso terapéutico , Resultado del Tratamiento , Trasplante Autólogo , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Estudios Retrospectivos , Estudios Observacionales como AsuntoRESUMEN
The concept of tumor immunosurveillance has raised prospects for natural killer cell-based immunotherapy of human cancer. The cure of acute myeloid leukemia may depend on eradication of leukemic stem cells, the self-renewing component of leukemia. Whether natural killer cells can recognize and lyse leukemic stem cells is not known. To develop strategies that effectively target acute myeloid leukemia-leukemic stem cells, we investigated anti-leukemic effects of human alloreactive single KIR(+) natural killer cells. Natural killer effectors with KIR specificity mismatched with respect to HLA class I allotype of target cells effectively recognized acute myeloid leukemia-leukemic stem cells defined phenotypically as CD34(+)CD38(-), while healthy bone marrow-derived CD34(+)CD38(-) hematopoietic stem cells were spared, as demonstrated by cytotoxicity and hematopoietic colony-forming assays. The HDAC inhibitor valproic acid increased the activating NKG2D ligand-dependent lysis of acute myeloid leukemia-CD34(+)CD38(-) leukemic stem cells. These results show that alloreactive natural killer cells have the potential to detect and target leukemic stem cells, and thus to improve the treatment outcome in acute myeloid leukemia.
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Células Madre Hematopoyéticas/inmunología , Células Asesinas Naturales/inmunología , Leucemia Mieloide Aguda/patología , Receptores de Células Asesinas Naturales , Células Madre Hematopoyéticas/patología , Antígenos de Histocompatibilidad Clase I , HumanosRESUMEN
Natural killer (NK) cells are potent effectors of innate antitumor defense and are currently exploited for immune-based therapy of human leukemia. However, malignant blood cells in acute myeloid leukemia (AML) display low levels of ligands for the activating immunoreceptor NKG2D and can thus evade NK immunosurveillance. We examined the possibility of up-regulating NKG2D-specific UL16-binding protein (ULBP) ligands using anti-neoplastic compounds with myeloid differentiation potential. Combinations of 5-aza-2'-deoxycytidine, trichostatin A, vitamin D3, bryostatin-1, and all-trans-retinoic acid, used together with myeloid growth factors and interferon-gamma, increased cell surface ULBP expression up to 10-fold in the AML cell line HL60 and in primary AML blasts. Up-regulation of ULBP ligands was associated with induction of myelomonocytic differentiation of AML cells. Higher ULBP expression increased NKG2D-dependent sensitivity of HL60 cells to NK-mediated killing. These findings identify NKG2D ligands as targets of leukemia differentiation therapy and suggest a clinical benefit in combining a pharmacological approach with NK cell-based immunotherapy in AML.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Citotoxicidad Inmunológica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Células Asesinas Naturales/inmunología , Leucemia Mieloide/metabolismo , Enfermedad Aguda , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Brioestatinas/administración & dosificación , Diferenciación Celular , Línea Celular Tumoral , Colecalciferol/administración & dosificación , Decitabina , Citometría de Flujo , Proteínas Ligadas a GPI , Humanos , Ácidos Hidroxámicos/administración & dosificación , Leucemia Mieloide/inmunología , Leucemia Mieloide/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tretinoina/administración & dosificación , Regulación hacia ArribaRESUMEN
BACKGROUND: Beta-1-->3-D-glucans represent a pathogen-associated molecular pattern and are able to modify biological responses. Employing a comprehensive methodological approach, the aim of our in vitro study was to elucidate novel molecular and cellular mechanisms of human peripheral blood immune cells mediated by a fungal beta-1-->3-D-glucan, i.e. glucan phosphate, in the presence of lipopolysaccharide (LPS) or toxic shock syndrome toxin 1 (TSST-1). RESULTS: Despite an activation of nuclear factor (NF) kappaB, NFinterleukin(IL)-6 and NFAT similar to LPS or TSST-1, we observed no significant production of IL-1beta, IL-6, tumor necrosis factor alpha or interferon gamma induced by glucan phosphate. Glucan phosphate-treated leukocytes induced a substantial amount of IL-8 (peak at 18 h: 5000 pg/ml), likely due to binding of NFkappaB to a consensus site in the IL-8 promoter. An increase in IL-1receptor antagonist (RA) production (peak at 24 h: 12000 pg/ml) by glucan phosphate-treated cells positively correlated with IL-8 levels. Glucan phosphate induced significant binding to a known NFIL-6 site and a new NFAT site within the IL-1RA promoter, which was confirmed by inhibition experiments. When applied in combination with either LPS or TSST-1 at the same time points, we detected that glucan phosphate elevated the LPS- and the TSST-1-induced DNA binding of NFkappaB, NFIL-6 and NFAT, leading to a synergistic increase of IL-1RA. Further, glucan phosphate modulated the TSST-1-induced inflammatory response via reduction of IL-1beta and IL-6. As a consequence, glucan phosphate shifted the TSST-1-induced IL-1beta/IL-1RA ratio towards an anti-inflammatory phenotype. Subsequently, glucan phosphate decreased the TSST-1-induced, IL-1-dependent production of IL-2. CONCLUSION: Thus, beta-1-->3-D-glucans may induce beneficial effects in the presence of pro-inflammatory responses, downstream of receptor binding and signaling by switching a pro- to an anti-inflammatory IL-1RA-mediated reaction. Our results also offer new insights into the complex regulation of the IL-1RA gene, which can be modulated by a beta-1-->3-D-glucan.
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ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/genética , Interleucina-1/biosíntesis , Interleucina-6/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Regiones Promotoras Genéticas , Sialoglicoproteínas/biosíntesis , beta-Glucanos/farmacología , Toxinas Bacterianas/farmacología , Sitios de Unión , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Secuencia de Consenso , Sinergismo Farmacológico , Ensayo de Cambio de Movilidad Electroforética , Enterotoxinas/farmacología , Humanos , Immunoblotting , Inflamación/metabolismo , Interferón gamma/biosíntesis , Interferón gamma/genética , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1/genética , Interleucina-6/genética , Interleucina-8/biosíntesis , Interleucina-8/genética , Interleucinas/genética , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , FN-kappa B/antagonistas & inhibidores , Factores de Transcripción NFATC/antagonistas & inhibidores , Unión Proteica/efectos de los fármacos , Proteoglicanos , Sialoglicoproteínas/genética , Superantígenos/farmacología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta1 , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
This study exploited alloreactivity of natural killer (NK) cells for augmenting the recognition of human acute myeloid leukemia (AML). To circumvent the inhibitory effect of killer immunoglobulin receptor (KIR) signaling, we generated NK-cell lines with single KIR specificities for major human leukocyte antigen (HLA) class I allotypes. We demonstrated efficient cytolysis of KIR-HLA class I-mismatched primary AML blasts even at low effector-to-target ratios. To define the impact of tumor-associated activating NKG2D-ligands (NKG2D-L), 66 AML patients at diagnosis were analyzed. NKG2D-L were selectively expressed on monoblastic cells in AML M4 and M5 yet absent or weakly expressed on myeloblastic cells in all AML subtypes. Paucity of cell-surface NKG2D-L was not the result of shedding because levels of soluble ULBP1 ligand measured in AML plasma were in the normal range. Notably, purified NKG2D-L(+) monoblastic cells were more susceptible to NK-mediated killing than NKG2D-L(-) myeloblastic cells. Accordingly, induction of cell-surface NKG2D-L by treatment with the histone deacetylase inhibitor, valproic acid, rendered cells more sensitive to NK cytolysis. These data suggest that adoptive transfer of selected populations of alloreactive HLA class I-mismatched NK cells in combination with pharmacologic induction of NKG2D-L merits clinical evaluation as novel approaches to immunotherapy of human AML.