RESUMEN
Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
Asunto(s)
Neoplasias de la Mama , Neoplasias Mamarias Animales , Humanos , Femenino , Animales , Epítopos/metabolismo , Vinorelbina/metabolismo , Vinorelbina/uso terapéutico , Receptor ErbB-2 , Neoplasias de la Mama/metabolismo , Inmunoterapia , Péptidos/metabolismo , Células Dendríticas , Trastuzumab/uso terapéutico , Trastuzumab/metabolismoRESUMEN
Hyperleukocytosis occurs in 15-20% of all newly diagnosed acute myeloid leukemia patients and requires emergent treatment with leukapheresis or hydroxyurea when accompanied by signs or symptoms of leukostasis. Currently, there is no standardized hydroxyurea dosing strategy, although usual dosing ranges from 50 to 150 mg/kg/day, and prescribing patterns vary significantly among oncologists and institutions. In addition to other hematologic and dermatologic toxicities, the use of hydroxyurea may be associated with significant mucositis and mucositis-related pain. The purpose of this study was to compare mucositis-related pain between two different hydroxyurea dosing strategies in patients who received hydroxyurea for cytoreduction during induction. A retrospective chart review of adult patients with acute myeloid leukemia treated with chemotherapy at UNC Medical Center from April 2014 to April 2016 who received at least one dose of hydroxyurea for cytoreduction was conducted. This study compared the safety and toxicity profiles of hydroxyurea in patients who received high-dose hydroxyurea (≥75 mg/kg/day) versus low-dose hydroxyurea (<75 mg/kg/day). Safety and toxicity were evaluated based on indicators of mucositis and cumulative intravenous narcotic requirements following induction chemotherapy. Data collection included baseline demographics, mucositis risk factors, baseline laboratory values, hydroxyurea dosing, mucositis indicators, and pain indicators. A total of 55 patients were included in the study, 21 patients (38.2%) received the high-dose hydroxyurea dosing strategy. The high-dose hydroxyurea dosing strategy had a significantly higher white blood cell count at diagnosis, increased duration of hydroxyurea, and received a higher cumulative dose of hydroxyurea. Additionally, the high-dose hydroxyurea dosing strategy patients were associated with significantly more grade 3 or 4 mucositis requiring a formulation change (0% versus 28.6%, p = 0.002) and significantly higher cumulative intravenous narcotic requirements during induction (p = 0.019). No significant differences in baseline demographics or mucositis risk factors between dosing strategies were identified. The high-dose hydroxyurea dosing strategy patients had a significant increase in cumulative intravenous narcotic requirements and formulation changes, both common interventions made for the treatment of mucositis. Additional studies are needed to further elucidate the safety and toxicity profiles of hydroxyurea dosing strategies and to explore the correlation between total cumulative hydroxyurea dose and total cumulative narcotic requirements.
Asunto(s)
Hidroxiurea/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucocitosis/tratamiento farmacológico , Mucositis/inducido químicamente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Fibrocytes are circulating, hematopoietic cells that express CD45 and Col1a1. They contribute to wound healing and several fibrosing disorders by mechanisms that are poorly understood. In this report, we demonstrate that fibrocytes predispose the lung to B16-F10 metastasis by recruiting Ly-6C(+) monocytes. To do so, we isolated fibrocytes expressing CD45, CD11b, CD13, and Col1a1 from the lungs of wild type (WT) and Ccr5(-/-) mice. WT but not Ccr5(-/-) fibrocytes increased the number of metastatic foci when injected into Ccr5(-/-) mice (73 ± 2 versus 32 ± 5; p < 0.001). This process was MMP9 dependent. Injection of WT enhanced GFP(+) fibrocytes also increased the number of Gr-1(Int), CD11b(+), and enhanced GFP(-) monocytes. Like premetastatic-niche monocytes, these recruited cells expressed Ly-6C, CD117, and CD45. The transfer of these cells into Ccr5(-/-) mice enhanced metastasis (90 ± 8 foci) compared with B cells (27 ± 2), immature dendritic cells (31 ± 6), or alveolar macrophages (28 ± 3; p < 0.05). WT and Ccl2(-/-) fibrocytes also stimulated Ccl2 expression in the lung by 2.07 ± 0.05- and 2.78 ± 0.36-fold compared with Ccr5(-/-) fibrocytes (1.0 ± 0.06; p < 0.05). Furthermore, WT fibrocytes did not increase Ly-6C(+) monocytes in Ccr2(-/-) mice and did not promote metastasis in either Ccr2(-/-) or Ccl2(-/-) mice. These data support our hypothesis that fibrocytes contribute to premetastatic conditioning by recruiting Ly-6C(+) monocytes in a chemokine-dependent process. This work links metastatic risk to conditions that mobilize fibrocytes, such as inflammation and wound repair.
Asunto(s)
Quimiocina CCL2/metabolismo , Neoplasias Pulmonares/secundario , Pulmón/patología , Monocitos/patología , Neoplasias/metabolismo , Neoplasias/patología , Animales , Antígenos CD/metabolismo , Linfocitos B/metabolismo , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Células Dendríticas/metabolismo , Células Dendríticas/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo , Receptores CCR2/metabolismo , Receptores CCR5/metabolismoRESUMEN
BACKGROUND: Hypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked. CASE PRESENTATION: We report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent. CONCLUSION: In this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.
Asunto(s)
Anemia , Trastornos Linfoproliferativos , Neoplasias de la Próstata , Aplasia Pura de Células Rojas , Macroglobulinemia de Waldenström , Humanos , Masculino , Anciano , Inhibidores de Puntos de Control Inmunológico , Macroglobulinemia de Waldenström/complicaciones , Macroglobulinemia de Waldenström/tratamiento farmacológico , Aplasia Pura de Células Rojas/inducido químicamente , Aplasia Pura de Células Rojas/tratamiento farmacológico , Aplasia Pura de Células Rojas/complicaciones , Anemia/inducido químicamente , Neoplasias de la Próstata/complicacionesRESUMEN
BACKGROUND AND OBJECTIVES: Novel, non-cytotoxic agents are driving a paradigm shift for treatment of older adults with acute myeloid leukemia (AML). Older patients who initially receive intensive cytotoxic induction may choose to not proceed with cytotoxic consolidation therapy. Lenalidomide is an orally-administered immunomodulatory small molecule with activity in AML and a favorable safety profile in older adults with active leukemia. We conducted a phase Ib study of lenalidomide as post-remission therapy in older adults and assessed its impact on geriatric functional domains. MATERIALS AND METHODS: Participants were patients with AML over age 60 years who had undergone induction therapy and were poor candidates for cytotoxic consolidation. Lenalidomide was administered for 28 days in three dose cohorts. A Bayesian dose-escalation method determined cohort assignment and maximum tolerated dose (MTD). Geriatric assessment (GA) was performed before and after the cycle of lenalidomide. RESULTS: Nineteen patients with median age 68 were treated with at least one 28-day course of lenalidomide. Dose-limiting toxicities were observed in three participants at 25 mg, zero participants at 35 mg, and one participant at 50 mg. MTD was 35 mg. Median relapse-free survival was 4.3 months. GA was completed before and after treatment in fifteen patients, demonstrating improved cognitive function and no changes in physical, psychological, or social function after lenalidomide. CONCLUSION: Lenalidomide can be safely administered to older adults with AML with preservation of functional domains important to older patients. Serial GA can be performed in a novel drug study as a tool to characterize treatment tolerability.
Asunto(s)
Lenalidomida , Leucemia Mieloide Aguda , Anciano , Antineoplásicos/efectos adversos , Teorema de Bayes , Estudios de Cohortes , Humanos , Lenalidomida/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Previously, our group has used a B16-F10 melanoma model to show that C-C chemokine receptor 5 (CCR5) knockout (CCR5(-/-)) mice form fewer pulmonary metastases than wild-type mice. This advantage can be eliminated by injecting CCR5(-/-) mice with wild-type pulmonary mesenchymal cells before tumor injection. In this article, we present the mechanisms underlying this finding. First, we demonstrate that wild-type mesenchymal cells migrate to CCL4 more efficiently in vitro than CCR5(-/-) cells. Wild-type mesenchymal cells were also 3.6 (1.85 to 5.85) times more efficient than CCR5(-/-) cells at migrating into the lung after intravenous injection (P < 0.01). The injection of wild-type but not CCR5(-/-) mesenchymal cells led to a 7.0 +/- 1.6 (P < 0.05)-fold induction of matrix metalloproteinase 9 (MMP9) in the host lung. Neither wild-type nor CCR5(-/-) cells caused significant increases in MMP2, MMP3, or MMP8. Inhibition of the gelatinase activity of MMP9 decreased the number of metastases and restored the advantage that CCR5(-/-) mice have over wild-type mice. Further analysis showed that the CCR5(+) mesenchymal cells expressed CD45(+) and CD13(+) but did not express alpha-smooth muscle actin. This phenotype is characteristic of a subset of mesenchymal cells called fibrocytes. Together, these data suggest a novel role for CCR5 in the migration of pulmonary fibrocytes and the promotion of metastasis.
Asunto(s)
Movimiento Celular/fisiología , Células del Tejido Conectivo/metabolismo , Neoplasias Pulmonares/secundario , Metaloproteinasa 9 de la Matriz/metabolismo , Metástasis de la Neoplasia/patología , Receptores CCR5/metabolismo , Animales , Western Blotting , Citometría de Flujo , Inmunohistoquímica , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Invasividad Neoplásica/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores CCR5/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Inflammatory cytokines have been implicated in the pathology of multiple neurologic diseases, including multiple sclerosis. We examined the role of the TNF family member TWEAK in neuroinflammation. Cuprizone-fed mice undergo neuroinflammation and demyelination in the brain, but upon removal of cuprizone from the diet, inflammation is resolved and remyelination occurs. Using this model, we demonstrate that mice lacking TWEAK exhibit a significant delay in demyelination and microglial infiltration. During remyelination, mice lacking the TWEAK gene demonstrate only a marginal delay in remyelination. Thus, this study identifies a primary role of TWEAK in promoting neuroinflammation and exacerbating demyelination during cuprizone-induced damage.
Asunto(s)
Enfermedades Desmielinizantes/fisiopatología , Encefalitis/fisiopatología , Factores de Necrosis Tumoral/fisiología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Quelantes/toxicidad , Cobre , Cuprizona/toxicidad , Citocina TWEAK , Enfermedades Desmielinizantes/inducido químicamente , Método Doble Ciego , Encefalitis/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , Vaina de Mielina/fisiología , Oligodendroglía/metabolismo , Oligodendroglía/patología , ARN Mensajero/biosíntesis , Receptores del Factor de Necrosis Tumoral/fisiología , Receptor de TWEAK , Factores de Necrosis Tumoral/biosíntesis , Factores de Necrosis Tumoral/deficiencia , Factores de Necrosis Tumoral/genéticaRESUMEN
BACKGROUND: Salvage regimens for patients with relapsed/refractory acute myeloid leukemia (rrAML) lack comparative data for superiority. Thus, we conducted a retrospective analysis of clofarabine-based (GCLAC; granulocyte colony-stimulating factor [filgrastim], clofarabine, high-dose cytarabine) versus cladribine-based (CLAG; cladribine, cytarabine, granulocyte colony-stimulating factor [filgrastim]) regimens in rrAML. PATIENTS AND METHODS: We identified 41 consecutive patients with rrAML who had received either GCLAC or CLAG from 2011 to 2014. The primary outcome measure was the complete remission (CR) rate defined according to the International Working Group criteria. The secondary outcomes included the proportion of patients who underwent allogenic stem cell transplantation and the rate of relapse-free survival and overall survival. RESULTS: We found no significant differences in the baseline characteristics of the patients treated with GCLAC (n = 22) or CLAG (n = 19). The outcomes with these 2 regimens were not significantly different. Patients treated with GCLAC had a CR/CR with incomplete blood count recovery rate of 64% compared with 47% for the patients treated with CLAG (P = .36). Of the GCLAC patients, 45% underwent allogeneic stem cell transplantation compared with 26% of the CLAG patients (P = .32). The median relapse-free survival after GCLAC and CLAG was 1.59 years and 1.03 years, respectively (P = .75). The median overall survival after GCLAG and CLAG was 1.03 years and 0.70 years, respectively (P = .08). The drug costs were significantly different for GCLAC versus CLAG. Using an average wholesale price, the cost per patient per cycle was $60,821.60 for GCLAC and $4910.60 for CLAG. CONCLUSION: A single-institutional retrospective analysis found no significant differences in the outcomes between GCLAC and CLAG for rrAML patients, although formal comparisons should be performed in a randomized clinical trial. The cost of GCLAC was greater than that of CLAG, which should be considered when evaluating the choice for the salvage chemotherapy options.
Asunto(s)
Cladribina/uso terapéutico , Clofarabina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Terapia Recuperativa/métodos , Cladribina/farmacología , Clofarabina/farmacología , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
We have shown that mice that express the C-C chemokine receptor 5 (CCR5) have enhanced local tumor growth and an impaired response to vaccine therapy compared with CCR5 knockout (CCR5(-/-)) mice. Here, we extend these observations to evaluate the function of CCR5 in pulmonary metastasis and the mechanism underlying the diminished tumor growth in CCR5(-/-) mice. Lung metastases were counted in wild-type (WT) and CCR5(-/-) mice following the injection of 1 x 10(6) B16-F10 melanoma cells. These results were compared with those from syngeneic bone marrow chimeric mice formed by the transfer of WT bone marrow into irradiated CCR5(-/-) and CCR5(-/-) marrow into irradiated WT mice. Intact CCR5(-/-) mice developed fewer metastases than WT mice (40.2 versus 70.6; P < 0.05). Bone marrow chimeras formed by the transfer of WT bone marrow into CCR5(-/-) hosts had fewer metastases than WT hosts injected with knockout marrow (46.6 versus 98.6; P < 0.01). Adoptive transfer of CCR5-expressing leukocytes also failed to promote metastasis in CCR5(-/-) mice. However, the i.v. transfer of WT pulmonary stromal cells into CCR5(-/-) mice increased the number of metastases compared with transfer of CCR5(-/-) stromal cells (102.8 versus 26.0; P < 0.05). These results show for the first time that CCR5 expression on stromal and not hematopoietic cells contributes to tumor metastasis. Therefore, recently developed CCR5 inhibitors may have a novel benefit in cancer therapy.
Asunto(s)
Neoplasias Pulmonares/secundario , Melanoma Experimental/secundario , Receptores CCR5/fisiología , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Inmunoterapia Adoptiva , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores CCR5/biosíntesis , Receptores CCR5/deficiencia , Células del Estroma/metabolismoRESUMEN
UNLABELLED: C-C Chemokine receptor 5 knockout (Ccr5(-/-)) mice develop fewer experimental pulmonary metastases than wild-type (WT) mice. This phenomenon was explored by applying gene expression profiling to the lungs of mice with these metastases. Consequently, erythroid differentiation regulator 1 (Erdr1) was identified as upregulated in the WT mice. Though commonly associated with bone marrow stroma, Erdr1 was differentially expressed in WT pulmonary mesenchymal cells (PMC) and murine embryonic fibroblasts (MEF). Moreover, the Ccr5 ligand Ccl4 increased its expression by 3.36 ± 0.14-fold. Ccr5 signaling was dependent on the mitogen-activated protein kinase kinase (Map2k) but not the phosphoinositide 3-kinase (Pi3k) pathway because treatment with U0126 inhibited upregulation of Erdr1, but treatment with LY294002 increased the expression by 3.44 ± 0.92-fold (P < 0.05). The effect Erdr1 on B16-F10 melanoma metastasis was verified by the adoptive transfer of WT MEFs into Ccr5(-/-) mice. In this model, MEFs that had been transduced with Erdr1 short hairpin RNA (shRNA) lowered metastasis by 33% compared with control transduced MEFs. The relevance of ERDR1 on human disease was assessed by coculturing chronic lymphocytic leukemia (CLL) cells with M2-10B4 stromal cells that had been transfected with shRNA or control plasmids. After 96 hours of coculture, the cell counts were higher with control cell lines than with Erdr1 knockdown lines [odds ratio (OR), 1.88 ± 0.27, 2.52 ± 0.66, respectively]. This increase was associated with a decrease in apoptotic cells (OR, 0.69 ± 0.18, 0.58 ± 0.12, respectively). IMPLICATIONS: Therefore, ERDR1 is a stromal-derived factor that promotes cancer cell survival in vitro and in an experimental metastasis model.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/metabolismo , Neoplasias Pulmonares/secundario , Proteínas de la Membrana/metabolismo , Células Madre Mesenquimatosas/metabolismo , Receptores CCR5/fisiología , Animales , Antagonistas de los Receptores CCR5 , Línea Celular Tumoral , Cromonas/farmacología , Técnicas de Cocultivo , Femenino , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Sistema de Señalización de MAP Quinasas , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfolinas/farmacología , Neoplasias Experimentales , ARN Interferente Pequeño/farmacología , Células Tumorales CultivadasRESUMEN
Clofarabine and gemtuzumab ozogamicin (GO) are active agents against acute myeloid leukemia (AML), but have not previously been tested in combination. We conducted a phase I study to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of clofarabine when combined with GO in adult patients with relapsed or refractory AML. Twenty patients received clofarabine (10, 20 or 30 mg/m(2)) on days 1-5, with GO 3 mg/m(2)/day on days 1, 4 and 7. Common dose-limiting toxicities were prolonged myelosuppression and hepatotoxicity. Clofarabine 20 mg/m(2) was the MTD, but with a DLT rate of 0.38 (5/13) - a rate that is prohibitively high to recommend for phase II study. The overall response rate (complete response [CR] + complete response with incomplete hematologic recovery [CRi]) was 42% among all patients. Thus, this combination demonstrated activity in relapsed and refractory patients, but further testing of the combination using lower doses of GO may identify more favorable rates of toxicity while maintaining efficacy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/efectos adversos , Adulto , Alanina Transaminasa/metabolismo , Aminoglicósidos/administración & dosificación , Aminoglicósidos/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversos , Aspartato Aminotransferasas/metabolismo , Clofarabina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Gemtuzumab , Humanos , Infusiones Intravenosas , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Recurrencia , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
The inflammasome is a proteolysis complex that generates the active forms of the proinflammatory cytokines interleukin (IL)-1ß and IL-18. Inflammasome activation is mediated by NLR proteins that respond to microbial and nonmicrobial stimuli. Among NLRs, NLRP3 senses the widest array of stimuli and enhances adaptive immunity. However, its role in antitumor immunity is unknown. Therefore, we evaluated the function of the NLRP3 inflammasome in the immune response using dendritic cell vaccination against the poorly immunogenic melanoma cell line B16-F10. Vaccination of Nlrp3(-/-) mice led to a relative 4-fold improvement in survival relative to control animals. Immunity depended on CD8(+) T cells and exhibited immune specificity and memory. Increased vaccine efficacy in Nlrp3(-/-) hosts did not reflect differences in dendritic cells but rather differences in myeloid-derived suppressor cells (MDSC). Although Nlrp3 was expressed in MDSCs, the absence of Nlrp3 did not alter either their functional capacity to inhibit T cells or their presence in peripheral lymphoid tissues. Instead, the absence of Nlrp3 caused a 5-fold reduction in the number of tumor-associated MDSCs found in host mice. Adoptive transfer experiments also showed that Nlrp3(-/-) MDSCs were less efficient in reaching the tumor site. Depleting MDSCs with an anti-Gr-1 antibody increased the survival of tumor-bearing wild-type mice but not Nlrp3(-/-) mice. We concluded that Nlrp3 was critical for accumulation of MDSCs in tumors and for inhibition of antitumor T-cell immunity after dendritic cell vaccination. Our findings establish an unexpected role for Nlrp3 in impeding antitumor immune responses, suggesting novel approaches to improve the response to antitumor vaccines by limiting Nlrp3 signaling.
Asunto(s)
Vacunas contra el Cáncer/inmunología , Proteínas Portadoras/inmunología , Células Dendríticas/inmunología , Inflamasomas/inmunología , Células Mieloides/inmunología , Linfocitos T Reguladores/inmunología , Animales , Vacunas contra el Cáncer/antagonistas & inhibidores , Vacunas contra el Cáncer/farmacología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/inmunología , Carcinoma Pulmonar de Lewis/terapia , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Línea Celular Tumoral , Movimiento Celular/inmunología , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLRAsunto(s)
Linfoma de Células B Grandes Difuso/microbiología , Linfoma de Células B Grandes Difuso/patología , Seno Maxilar/patología , Anciano , Preescolar , Clostridioides difficile/aislamiento & purificación , Enterocolitis Seudomembranosa/tratamiento farmacológico , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Femenino , Humanos , Persona de Mediana Edad , Remisión EspontáneaRESUMEN
We sought to evaluate the temporal pattern of expression of important immune signaling genes in patients with varied TBSA burn injury during the first week after burn. Peripheral blood mononuclear cell fractions were collected from each patient (N = 10) at two time points, one immediately following burn injury, and the other 1 week later. The change in gene expression was correlated with all clinical data including burn size. It was found that gene expression was indirectly proportional with burn size. Smaller burns (<30%) TBSA resulted in an up-regulation of several genes measured, while larger burns (>30%) TBSA resulted in significant down-regulation. In conclusion, a larger burn establishes conditions for severe immunosuppression by down-regulating key immune signaling genes and could be one explanation for the increased susceptibility of major burns to infection. These data shed light on the etiology of burn-induced immune dysfunction in humans and support a more comprehensive genomic profile study in burn patients.
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Quemaduras/metabolismo , Regulación hacia Abajo , Perfilación de la Expresión Génica , Adolescente , Adulto , Anciano , Quemaduras/patología , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Infección Hospitalaria/microbiología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Proteína Adaptadora de Señalización NOD1/genética , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Infecciones Oportunistas/microbiología , Reacción en Cadena de la Polimerasa , ARN Mensajero/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismoRESUMEN
Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.
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Antibióticos Antineoplásicos/administración & dosificación , Ácidos Borónicos/administración & dosificación , Doxorrubicina/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Proteasas/administración & dosificación , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ácidos Borónicos/efectos adversos , Ácidos Borónicos/farmacocinética , Bortezomib , Doxorrubicina/efectos adversos , Doxorrubicina/farmacocinética , Femenino , Humanos , Liposomas , Masculino , Persona de Mediana Edad , Polietilenglicoles , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasoma , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Resultado del TratamientoRESUMEN
The translocation t(14;18)(q32;q21) is most commonly associated with follicular lymphoma but has also been described in acute lymphoblastic leukemia (ALL) of B-cell origin. Although these ALL cases have had a pre-pre-B, pre-B, or mature B-cell immunophenotype and L2 or L3 morphology, all have been associated with an abnormality of 8q24. In fact, 91% (10 of 11) have been associated with t(8;22) or t(8;14), marker chromosomes for Burkitt-type ALL. The other case was associated with del(8)(q24). Thus, Burkitt-type ALL may have various immunophenotypes and morphology when associated with t(14;18). We describe a case of mature B-cell ALL associated with t(14;18) and t(8;9)(q24;p13). The morphology was suggestive but not entirely characteristic of the L3 subtype. However, on the basis of the cytogenetic findings and the review of the literature, perhaps this case represents a variant of Burkitt-type ALL, which would be important to recognize for prognostic and therapeutic purposes. We describe our findings and review the literature to heighten awareness of this group of ALLs associated with t(14;18). Additional cases need to be accrued and documented to determine the significance of an associated abnormality of 8q24 in this setting.
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Linfoma de Burkitt/genética , Translocación Genética/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Análisis Citogenético/métodos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Macrophage inflammatory protein 1 alpha (MIP-1 alpha), a CC chemokine, is a chemoattractant for T cells and immature dendritic cells. Plasmacytoma cells expressing MIP-1 alpha generate a cytotoxic T cell response without affecting tumor growth. To understand this discrepancy, we compared a local tumor model with a metastatic one using MIP-1 alpha-transfected B16 F10 melanoma cells. Clonal idiosyncrasies were controlled by selecting three lipotransfected tumor clones and two pcDNA vector transfected control clones with equivalent in vitro proliferative capacities. No significant differences were seen between the MIP-1 alpha-producing and control melanoma cells after s.c. injection in the hind leg. All animals had a leg diameter of 10 cm in 18.5-21.5 days. However, after i.v. injection the number of pulmonary foci was significantly reduced in the MIP-1 alpha-producing clones. Injection of 10(6) control transfected cells resulted in a median of 98.5 tumor foci in 2 wk, whereas the injection of the MIP-1 alpha-producing clones resulted in 89.5, 26.5, and 0 foci. The number of metastatic foci was inversely proportional to the amount of MIP-1 alpha produced by the clone in vitro. Flow cytometry showed a significant increase in CD8(+) cells in lungs of mice with MIP-1 alpha-transfected tumors 3 days after injection. This increase was not maintained 10 days later despite continued production of MIP-1 alpha. The protection offered by transfection with MIP-1 alpha was significantly impaired in beta(2)-microglobulin(-/-) mice. Our findings suggest that MIP-1 alpha is effective in preventing the initiation of metastasis, but not at sustaining an effective antitumor response.
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Neoplasias Pulmonares/prevención & control , Neoplasias Pulmonares/secundario , Proteínas Inflamatorias de Macrófagos/uso terapéutico , Melanoma Experimental/patología , Neoplasias Cutáneas/prevención & control , Animales , Linfocitos T CD8-positivos/fisiología , División Celular , Quimiocina CCL3 , Quimiocina CCL4 , Femenino , Proteínas Inflamatorias de Macrófagos/genética , Ratones , Ratones Endogámicos C57BL , TransfecciónRESUMEN
We studied 28 patients with accelerated phase chronic myelogenous leukemia (CML) who were enrolled on the Novartis expanded access study 114. Diagnosis of accelerated phase CML was based on karyotypic evolution (n = 9) and hematologic criteria (n = 18). All patients were begun on 600 mg/day of imatinib mesylate. Dose reductions to 400 mg/day and then 300 mg/day were prescribed for an absolute neutrophil count (ANC) of <0.5/microl or a platelet count of <20,000/microl. Twenty-seven of the 28 patients continued treatment for a median of 34 weeks. Eleven patients developed thrombocytopenia following an average of 8.4 +/- 1.4 weeks of therapy. The onset of thrombocytopenia was associated with disease progression in one patient and a decline in bone marrow megakaryocytes in the other 10. Nine patients recovered to a platelet count of >20,000/microl after an average of 19.7 +/- 1.8 weeks. Patients who developed thrombocytopenia had a longer duration of disease (9.39 vs. 4.35 years; P < 0.01) and were more likely to be diagnosed with accelerated phase CML by hematologic criteria. Hematologic responses in patients with and without thrombocytopenia were comparable; however, 31.3% of patients without thrombocytopenia had a complete cytogenetic response compared to none of those with thrombocytopenia. Grade III-IV thrombocytopenia is common in accelerated phase CML and may be a marker for the inability to achieve cytogenetic response using single agent imatinib mesylate.