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2.
Mol Biol (Mosk) ; 53(5): 774-789, 2019.
Artículo en Ruso | MEDLINE | ID: mdl-31661477

RESUMEN

Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and acts as a danger signal. IL-33 is released from stressed or necrotic cells. Initially, IL-33 was described as an inducer of the humoral immune response, which activated Th2 cells and mast cells involved in modulating inflammation and allergic reactions. In addition, IL-33 acts as a stimulator of the Th1, NK, and CD8T cells, which induce a cytotoxic immune response against intracellular pathogens. It was recently discovered that this cytokine is involved in the development of cancer by performing both pro- and antitumor functions. IL-33 can directly affect tumor cells and provokes their proliferation, survival, and metastasis. Moreover, IL-33 stimulates carcinogenesis by remodeling the tumor microenvironment and inducing angiogenesis, thus contributing to the generation of immunosuppressive conditions. At the same time, IL-33 causes tumor infiltration with cytotoxic CD8 T lymphocytes and natural killers, which leads to cytolysis-mediated cancer cell death. This review describes the versatile role of the IL-33/ST2 cascade in the development of experimental and clinical tumors. In addition, we discuss the prospects for the application of IL-33 and ST2 as diagnostic biomarkers and targets for cancer immunotherapy.


Asunto(s)
Inmunoterapia/métodos , Interleucina-33/inmunología , Neoplasias/inmunología , Neoplasias/patología , Escape del Tumor/inmunología , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/diagnóstico , Neovascularización Patológica , Microambiente Tumoral/inmunología
3.
Mol Biol (Mosk) ; 53(5): 849-859, 2019.
Artículo en Ruso | MEDLINE | ID: mdl-31661483

RESUMEN

T cells play a key role in adaptive immunity reactions, recognizing antigens using variable TCRs. Functional TCR subunit genes are formed by somatic rearrangement, and some of the resulting TCRs recognize autoantigens, the body's own molecules. The autoreactive T cells that carry such TCRs pose a threat of inducing immune reactions against their own organism. In the course of the immune system's development, some autoreactive T lymphocytes are eliminated by apoptosis, some differentiate into immunosuppressive regulatory T cells, which support immunological tolerance to autoantigens, and the rest fall into a non-functional state of anergy. Suppression of effector T cells by regulatory T cells is mediated by immunosuppressive cytokines and costimulatory molecules, depletion of stimulating IL-2, removal of autoreactive peptides together with MHC molecules, and in other ways. Impairment of self-tolerance leads to autoimmune diseases. However, the loss of immunological tolerance can be employed in tumor treatment, allowing immunotherapy and the use of the potential of autoreactive effector T cells. The fact that the efficacious immunotherapy of tumors is often accompanied by adverse autoimmune reactions currently seems to be the inevitable price paid by using this approach.


Asunto(s)
Autoantígenos/inmunología , Epítopos/inmunología , Linfocitos T/inmunología , Enfermedades Autoinmunes/inmunología , Humanos , Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Autotolerancia/inmunología
4.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31593084

RESUMEN

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Enfermedades del Sistema Inmune/inducido químicamente , Inmunoterapia/efectos adversos , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Femenino , Humanos , Enfermedades del Sistema Inmune/inmunología , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Retrospectivos
5.
Medicine (Baltimore) ; 98(38): e17228, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31567984

RESUMEN

OBJECTIVE: To determine whether psychological intervention (PI) changes the levels of immune indicators in cancer patients. METHODS: We conducted a systematic search published up to July 2018, followed by a manual search. Randomized controlled trials were included. Two reviewers independently screened and extracted data, which were analyzed using Review manager 5.3. RESULTS: Twenty-nine studies were included including four kinds of PI. Only stress management didn't result in immune changes; only cognitive behavior therapy affect NK cell activity. PI did not change immune indicators on cancer patients who completed therapy. Compared to patients not receiving PI, those received PI had significantly higher NK cell count and activity in whole blood; and serum levels of IL-2, IL-4, IFN-γ, lgA, and lgG. However, the differences in the serum levels of IL-6, IL-10, TNF-α, and IgM were not significant (P > .05), and the changes recorded for the CD3, CD4, and CD8 cell count, and CD4/CD8 ratios were inconsistent. CONCLUSIONS: Although there are considerable evidences of PI's immune effect, but its magnitude was moderate. Therefore, it may be premature to conclude whether PI affects immunity of cancer patients. Further research is warranted, with special focus on the PI types and treatment methods.


Asunto(s)
Neoplasias/psicología , Psicoterapia , Humanos , Inmunidad , Neoplasias/inmunología , Neoplasias/terapia , Psicoterapia/métodos
6.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3129-3134, 2019 Aug.
Artículo en Chino | MEDLINE | ID: mdl-31602863

RESUMEN

The best time of tumor intervention is before the formation of tumor. However,due to the limited number of tumor cells,it is difficult to quantify tumor cells and immunity by the current methods available( such as CTC,ct DNA). This affects the tumor prevention in this period,and the in-depth detection,intervention and evaluation of traditional Chinese medicine( TCM)( tumor) prevention. Due to the limitations of the current detection,the evaluation system turns to detect tumor neoantigen-specific CTL( naCTL) that are directly relating to tumor cells and proliferate to high order of magnitudes after activation,and immune repertoire( TCR/BCR/HLA) effective diversity,introduces immune checkpoints,uses information of " disease" in Western medicine and " syndrome" in TCM( prevention),and sets up a multi-dimensional statistical immunity model using a variety of data analysis and related algorithms. This model can amplify the ultra-early information of tumor,indirectly evaluate the quantity and status of tumor cells,and provide quantitative measurement and new evaluation methods for the normalization of immunity and TCM( tumor) prevention. This model is not only one of important evaluation methods for resisting tumor immunity and treating TCM( tumor) prevention,but also will reveal the scientific connotation of TCM syndrome from the perspective of immunology.


Asunto(s)
Medicamentos Herbarios Chinos , Neoplasias/inmunología , Neoplasias/prevención & control , Antígenos HLA , Humanos , Medicina China Tradicional , Receptores de Antígenos de Linfocitos B , Receptores de Antígenos de Linfocitos T
7.
Med Oncol ; 36(11): 94, 2019 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-31605245

RESUMEN

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a variety of solid tumors; nonetheless, they have not been well investigated and are still recognized as a relative contraindication for patients with a liver transplantation (LT) history, since ICIs treatment might potentially lead to graft rejection. The program death-1 (PD-1) and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways are implicated in the tolerance of transplanted organ, as well as blockade of the pathways, which contribute to eliminating tumors and may inadvertently lead to peripheral transplant rejection. Currently, no guidelines are available regarding the treatment for ICIs patients with a prior LT history. Therefore, this study was carried out to review the recent studies, attempting to introduce the ICIs-related graft rejection after LT from various aspects. We believed that ICIs could be given for the well-informed patients receiving LT and developed recurrence in a controlled setting. Typically, these patients should be treated according to a clinical care path or a prospective clinical trial, so as obtain a persistent anti-tumor immune response in the meantime of avoiding graft rejection, adjust the immunosuppression, reduce the possibility of graft loss following rejection, and have the opportunity to develop biomarkers for tumor response and transplant rejection.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Rechazo de Injerto/inducido químicamente , Trasplante de Hígado , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Rechazo de Injerto/inmunología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología
8.
Cancer Immunol Immunother ; 68(10): 1605-1619, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31531696

RESUMEN

The main effectors in tumor control are the class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1+CD141+ appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1+CD141+ molecules with a cross-presentation function in humans. Thus, if tolerogenic DCs can be reactivated into immunogenic DCs with sufficient co-stimulatory molecules, tumor-specific CD8+ CTLs can be primed and activated in vivo. In the present study, we converted human tolerogenic CD141+ DCs with enhanced co-stimulatory molecule expression of CD40, CD80, and CD86 through stimulation with non-toxic mycobacterial lipids such as mycolic acid (MA) and lipoarabinomannan (LAM), which synergistically enhanced both co-stimulatory molecule expression and interleukin (IL)-12 secretion by XCR1+CD141+ DCs. Moreover, MA and LAM-stimulated DCs captured tumor antigens and presented tumor epitope(s) in association with class I MHCs and sufficient upregulated co-stimulatory molecules to prime naïve CD3+ T cells to become CD8+ tumor-specific CTLs. Repeat CD141+ DC stimulation with MA and LAM augmented the secretion of IL-12. These findings provide us a new method for altering the tumor environment by converting tolerogenic DCs to immunogenic DCs with MA and LAM from Mycobacterium tuberculosis.


Asunto(s)
Células Dendríticas/inmunología , Lipopolisacáridos/farmacología , Mycobacterium/química , Ácidos Micólicos/farmacología , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Antígenos de Superficie/análisis , Línea Celular Tumoral , Células Dendríticas/efectos de los fármacos , Humanos , Interleucina-12/biosíntesis , Mycobacterium bovis
9.
Medicine (Baltimore) ; 98(37): e17019, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31517821

RESUMEN

The role of cytokines in the systemic inflammatory response (SIR) is now well established. This is in keeping with the role of the SIR in tumorigenesis, malignant spread, and the development of cachexia. However, the relationship between performance status/systemic inflammation frameworks and cytokine profiles is not clear. The aim of the present study was to examine the relationship between the Eastern cooperative oncology group performance status/modified Glasgow prognostic score (ECOG-PS/mGPS) and cooperative oncology group performance status/neutrophil platelet score (ECOG-PS/NPS) frameworks and their cytokine profile in patients with advanced cancer.This was a retrospective interrogation of data already collected as part of a recent clinical trial (NCT00676936). The relationship between the independent variables (ECOG-PS/mGPS and ECOG-PS/NPS frameworks), and dependent variables (cytokine levels) was examined using independent Mann-Whitney U and Kruskal Wallis tests where appropriate.Of the 40 patients included in final analysis the majority had evidence of an SIR assessed by mGPS (78%) or NPS (53%). All patients died on follow-up and the median survival was 91 days (4-933 days). With increasing ECOG-PS there was a higher median value of Interleukin 6 (IL-6, P = .016) and C-reactive protein (CRP, P < .01) and lower albumin (P < .01) and poorer survival (P < .001). With increasing mGPS there was a higher median value of IL-6 (P = .016), Macrophage migration inhibitory factor (MIF, P = .010), erythrocyte sedimentation rate (ESR, P < .01) and poorer survival (P < .01). With increasing NPS there was a higher median value of TGF-ß (P < .001) and C-reactive protein (P = .020) and poor survival (P = .001). When those patients with an ECOG-PS 0/1 and mGPS0 were compared with those patients with an ECOG-PS 2 and mGPS2 there was a higher median value of IL-6 (P = .017) and poorer survival (P < .001). When those patients with an ECOG-PS 0/1 and NPS0 were compared with those patients with an ECOG-PS 2 and NPS1/2 there was a higher median value of IL-6 (P = .002), TGF-ß (P < .001) and poorer survival (P < .01).In patients with advanced cancer IL-6 was associated with the ECOG-PS/mGPS and ECOG-PS/NPS frameworks and survival in patients with advanced cancer. Therefore, the present work provides supporting evidence that agents targeting IL-6 are worthy of further exploration.


Asunto(s)
Citocinas/inmunología , Inflamación/inmunología , Neoplasias/inmunología , Anciano , Biomarcadores/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inflamación/diagnóstico , Inflamación/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/mortalidad , Neoplasias/terapia , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia
11.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31519568

RESUMEN

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Neoplasias/mortalidad , Compuestos Organometálicos/farmacología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Estimación de Kaplan-Meier , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Tomografía Computarizada por Rayos X
12.
J Cancer Res Clin Oncol ; 145(10): 2625-2631, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31492984

RESUMEN

PURPOSE: Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs. METHODS: In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables. RESULTS: At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1-70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (P < 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms. CONCLUSION: CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Biomarcadores , Proteína C-Reactiva , Inmunomodulación , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/metabolismo , Adulto Joven
13.
Isr Med Assoc J ; 21(7): 480-486, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31507125

RESUMEN

BACKGROUND: Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for SjÓ§gren's syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.


Asunto(s)
Hepatitis B/inmunología , Hepatitis C/inmunología , Factor Reumatoide/inmunología , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Crioglobulinemia/inmunología , Humanos , Trastornos Linfoproliferativos/inmunología , Neoplasias/inmunología , Factor Reumatoide/sangre
14.
Int J Nanomedicine ; 14: 4541-4558, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31417257

RESUMEN

Background: Tumor metastasis is responsible for most cancer death worldwide, which lacks curative treatment. Purpose: The objective of this study was to eliminate tumor and control the development of tumor metastasis. Methods: Herein, we demonstrated a smart nano-enabled platform, in which 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2h-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR780) and tirapazamine (TPZ) were co-loaded in poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL) to form versatile nanoparticles (PEG-PCL-IR780-TPZ NPs). Results: The intelligence of the system was reflected in the triggered and controlled engineering. Specially, PEG-PCL not only prolonged the circulation time of IR780 and TPZ but also promoted tumor accumulation of nanodrugs through enhanced permeability and retention (EPR) effect. Moreover, reactive oxygen species (ROS) generated by IR780 armed by an 808 nm laser irradiation evoked a cargo release. Meanwhile, IR780, as a mitochondria-targeting phototherapy agent exacerbated tumor hypoxic microenvironment and activated TPZ for accomplishing hypoxia-activated chemotherapy. Most significantly, IR780 was capable of triggering immunogenic cell death (ICD) during the synergic treatment. ICD biomarkers as a "danger signal" accelerated dendritic cells (DCs) maturation, and subsequently activated toxic T lymphocytes. Conclusion: Eventually, antitumor immune responses stimulated by combinational phototherapy and hypoxia-activated chemotherapy revolutionized the current landscape of cancer treatment, strikingly inhibiting tumor metastasis and providing a promising prospect in the clinical application.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Fototerapia , Animales , Antineoplásicos/farmacología , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Inmunoterapia , Indoles/uso terapéutico , Liposomas , Ratones Endogámicos BALB C , Nanopartículas/química , Nanopartículas/ultraestructura , Fotoquimioterapia , Fototerapia/métodos , Polietilenglicoles/química , Especies Reactivas de Oxígeno/metabolismo , Temperatura Ambiental , Tirapazamina/farmacología , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos
15.
Cancer Immunol Immunother ; 68(9): 1467-1477, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31451841

RESUMEN

BACKGROUND: The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors. METHODS: Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion. RESULTS: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment. CONCLUSIONS: Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Células Dendríticas/inmunología , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Piridinas/uso terapéutico , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Células Dendríticas/trasplante , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/mortalidad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Estudios Prospectivos , Piridinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Análisis de Supervivencia
16.
J Cancer Res Clin Oncol ; 145(10): 2541-2546, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31367835

RESUMEN

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is known to be prognostic for patients with advanced cancers treated with immune checkpoint inhibitors (ICI), but has generally been evaluated as a single threshold value at baseline. We evaluated NLR at baseline and within first month during treatment in patients who received ICI for advanced cancer to evaluate the prognostic value of baseline and of changes from baseline to on-treatment NLR. METHODS: A retrospective review of patients with advanced cancer treated with ICI from 2011 to 2017 at the Ohio State University was performed. NLR was calculated at the initiation of ICI and repeated at median of 21 days. Overall survival (OS) was calculated from the initiation of ICI to date of death or censored at last follow-up. Significance of Cox proportional hazards models were evaluated by log-rank test. Calculations were performed using the survival and survminer packages in R, and SPSS. RESULTS: 509 patients were identified and included in the analysis. Patients with baseline and on-treatment NLR < 5 had significantly longer OS (P < 0.001). The change in NLR overtime was a predictor of OS and was observed to be non-linear in nature. This property remained statistically significant with P < 0.05 after adjusting for age, body mass index, sex, cancer type, performance status, and days to repeat NLR measurement. Patients with a moderate decrease in NLR from baseline had the longest OS of 27.8 months (95% CI 21.8-33.8). Patients with significant NLR decrease had OS of 11.4 months (95% CI 6.1-16.7). Patients with a significant increase in NLR had the shortest OS of 5.0 months (95% CI 0.9-9.1). CONCLUSIONS: We confirmed the prognostic value of NLR in patients with advanced cancer treated with ICIs. We found that change in NLR over time is a non-linear predictor of patient outcomes. Patients who had moderate decrease in NLR during treatment with ICI were found to have the longest survival, whereas a significant decrease or increase in NLR was associated with shorter survival. To our knowledge, this is the first study to demonstrate a non-linear change in NLR over time that correlates with survival.


Asunto(s)
Recuento de Leucocitos , Recuento de Linfocitos , Linfocitos , Neoplasias/sangre , Neoplasias/mortalidad , Neutrófilos , Adulto , Anciano , Biomarcadores , Femenino , Humanos , Inmunoterapia , Estimación de Kaplan-Meier , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Neoplasias/terapia , Neutrófilos/inmunología , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
17.
DNA Cell Biol ; 38(10): 1040-1047, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31414895

RESUMEN

The helper T cell 9 (Thelper-9, Th9), as a functional subgroup of CD4+T cells, was first discovered in 2008. Th9 cells expressed transcription factor PU.1 and cytokine interleukin-9 (IL-9) characteristically. Recent researches have shown that the differentiation of Th9 cells was coregulated by cytokine transforming growth factor ß, IL-4, and various transcription factors. Th9 cells, as a new player, played an important role in various immune-related diseases, including tumors, inflammatory diseases, parasite infection, and other diseases. In this article, we summarize the related research progress and discuss the possible prospect.


Asunto(s)
Interleucina-9/inmunología , Lupus Eritematoso Sistémico/inmunología , Neoplasias/inmunología , Proteínas Proto-Oncogénicas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Transactivadores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Diferenciación Celular , Factor de Transcripción GATA3/deficiencia , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/inmunología , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-9/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Noqueados , Neoplasias/genética , Neoplasias/patología , Proteínas Proto-Oncogénicas/genética , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores/patología , Transactivadores/genética , Factor de Crecimiento Transformador beta/genética
18.
Cancer Sci ; 110(10): 3079-3088, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31432594

RESUMEN

Chimeric antigen receptor-engineered T (CAR-T)-cell therapy holds significant promise for the treatment of hematological malignancies, especially for B-cell leukemia and lymphoma. However, its efficacy against non-hematological malignancies has been limited as a result of several biological problems characteristic of the tumor microenvironment of solid tumors. One of the main hurdles is the heterogeneous nature of tumor-associated antigens (TAA) expressed in solid tumors. Another hurdle is the inefficient activation and limited persistence of CAR-T cells, mainly as a result of T-cell exhaustion caused by immunosuppressive factors in the tumor microenvironment. In the present study, to address these problems, we engineered CAR-T cells to produce antagonistic anti-programmed cell death protein 1 (PD-1) single-chain variable fragment (scFv), by which PD-1-dependent inhibitory signals in CAR-T cells and adjacent tumor-specific non-CAR-T cells are attenuated. In mouse solid tumor models, PD-1 scFv-producing CAR-T cells induced potent therapeutic effects superior to those of conventional CAR-T cells, along with a significant reduction of apoptotic cell death not only in CAR-T cells themselves but also in TAA-specific T cells in the tumor tissue. In addition, the treatment with anti-PD-1 scFv-producing CAR-T cells resulted in an increased concentration of PD-1 scFv in tumor tissue but not in sera, suggesting an induction of less severe systemic immune-related adverse events. Hence, the present study developed anti-PD-1 scFv-producing CAR-T cell technology and explored its cellular mechanisms underlying potent antitumor efficacy.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Anticuerpos de Cadena Única/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Técnicas de Cocultivo , Masculino , Ratones , Neoplasias/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Vet Immunol Immunopathol ; 214: 109902, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31378221

RESUMEN

Autoantibodies against cytokines have been associated with immunodeficiency, susceptibility to infectious diseases, autoimmunity and inflammation in humans, but have not yet been investigated in the Veterinary field so far. The aim of the current study was to determine the presence of anti-cytokine autoantibodies in canines suffering from various conditions including recurrent infections, autoimmune diseases and cancer in comparison to healthy controls. This is the first report of the presence of autoantibodies against cytokines in dogs. A total of 101 serum samples (51 patients and 50 clinically healthy dogs) from the state of Mexico and surroundings were analysed using a multiplex bead-based flow cytometry assay. Results show significant levels of various anti-cytokine autoantibodies in diseased dogs but not in healthy controls. In addition we show distinct associations of various disease types to the specificity of anti-cytokine autoantibodies and to response complexities. Apart from the direct functional/causal implication of anti-cytokine auto-antibodies on disease processes, this findings point to the possibility to use anti-cytokine response patterns as diagnostic tools.


Asunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes/veterinaria , Citocinas/inmunología , Enfermedades del Sistema Inmune/veterinaria , Animales , Enfermedades Autoinmunes/inmunología , Perros , Femenino , Enfermedades del Sistema Inmune/inmunología , Incidencia , Masculino , México , Neoplasias/inmunología , Neoplasias/veterinaria
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