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1.
J Immunother Cancer ; 8(1)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32209603

RESUMO

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

2.
Biomedicines ; 7(3)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480379

RESUMO

Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the successful production of NDV according to Good Manufacturing Practice (GMP). Based on this, IOZK in Cologne, Germany, obtained a GMP certificate for the production of a dendritic cell vaccine loaded with tumor antigens from a lysate of patient-derived tumor cells together with immunological danger signals from NDV for intracutaneous application. This update includes single case reports and retrospective analyses from patients treated at IOZK. The review also presents future perspectives, including the concept of in situ vaccination and the combination of NDV or other oncolytic viruses with checkpoint inhibitors.

3.
Anticancer Res ; 39(4): 2043-2051, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952748

RESUMO

BACKGROUND/AIM: The need for more effective treatment modalities that can improve the clinical outcome of patients with glioblastoma multiforme remains imperative. Dendritic cell vaccination is a fast-developing treatment modality, currently under exploration. Functional immune cell subpopulations may play a role in the final outcome. MATERIALS AND METHODS: Data from 101 patients drawn from the HGG-2010 trial, including baseline patient characteristics and fluorescence-activated cell sorting of immune cell subpopulations, were analyzed by statistical and machine-learning methods. RESULTS: The analysis revealed strong correlations between immune profiles and overall survival, when the extent of resection and the vaccination schedule were used as stratification variables. CONCLUSION: A systematic, in silico workflow detecting strong and statistically significant correlations between overall survival and immune profile-derived quantities obtained at the start of dendritic cell vaccination was devised. The derived correlations could serve as a basis for the identification of prognostic markers discriminating between potential long- and short-term survivors of patients with glioblastoma multiforme.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Células Dendríticas/imunologia , Glioblastoma/imunologia , Glioblastoma/terapia , Temozolomida/uso terapêutico , Adulto , Idoso , Terapia Combinada , Feminino , Citometria de Fluxo , Humanos , Imunoterapia , Leucaférese , Masculino , Pessoa de Meia-Idade , Fenótipo , Resultado do Tratamento , Vacinação
4.
Lancet Oncol ; 19(8): e419-e428, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102236

RESUMO

Paediatric CNS tumours are the most common cause of childhood cancer-related morbidity and mortality, and improvements in their diagnosis and treatment are needed. New genetic and epigenetic information about paediatric CNS tumours is transforming the field dramatically. For most paediatric CNS tumour entities, subgroups with distinct biological characteristics have been identified, and these characteristics are increasingly used to facilitate accurate diagnoses and therapeutic recommendations. Future treatments will be further tailored to specific molecular subtypes of disease, specific tumour predisposition syndromes, and other biological criteria. Successful biomaterial collection is a key requirement for the application of contemporary methodologies for the validation of candidate prognostic factors, the discovery of new biomarkers, the establishment of appropriate preclinical research models for targeted agents, a quicker clinical implementation of precision medicine, and for other therapeutic uses (eg, for immunotherapies). However, deficits in organisational structures and interdisciplinary cooperation are impeding the collection of high-quality biomaterial from CNS tumours in most centres. Practical, legal, and ethical guidelines for consent, storage, material transfer, biobanking, data sharing, and funding should be established by research consortia and local institutions to allow optimal collection of primary and subsequent tumour tissue, body fluids, and normal tissue. Procedures for the collection and storage of biomaterials and related data should be implemented according to the individual and organisational structures of the local institutions.


Assuntos
Bancos de Espécimes Biológicos/normas , Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central , Oncologia/normas , Pesquisa Médica Translacional/métodos , Bancos de Espécimes Biológicos/ética , Bancos de Espécimes Biológicos/organização & administração , Criança , Feminino , Humanos , Masculino , Oncologia/organização & administração , Oncologia/tendências , Pesquisa Médica Translacional/organização & administração , Pesquisa Médica Translacional/normas
5.
Sci Rep ; 7(1): 13902, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29066810

RESUMO

Immunotherapeutic strategies for glioblastoma, the most frequent malignant primary brain tumor, aim to improve its disastrous consequences. On top of the standard treatment, one strategy uses T cell activation by autologous dendritic cells (DC) ex vivo loaded with tumor lysate to attack remaining cancer cells. Wondering whether 'targeting' in vivo DCs could replace these ex vivo ones, immunogenic autologous tumor lysate was used to treat glioma-inoculated mice in the absence of ex vivo loaded DCs. Potential immune mechanisms were studied in two orthotopic, immunocompetent murine glioma models. Pre-tumoral subcutaneous lysate treatment resulted in a survival benefit comparable to subcutaneous DC therapy. Focussing on the immune response, glioma T cell infiltration was observed in parallel with decreased amounts of regulatory T cells. Moreover, these results were accompanied by the presence of strong tumor-specific immunological memory, shown by complete survival of a second glioblastoma tumor, inoculated 100 days after the first one. Finally, in combination with temozolomide, survival of established glioma in mice could be increased. Our results show the potential of immunogenic autologous tumor lysate used to treat murine glioblastoma, which will be worthwhile to study in clinical trials as it has potential as a cost-efficient adjuvant treatment strategy for gliomas.


Assuntos
Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Células Dendríticas/imunologia , Glioblastoma/imunologia , Glioblastoma/terapia , Imunoterapia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Terapia Combinada , Células Dendríticas/citologia , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sobrevida , Linfócitos T/imunologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico
6.
Int J Cancer ; 141(9): 1891-1900, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28681455

RESUMO

Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Glioma/tratamento farmacológico , Linfócitos do Interstício Tumoral/patologia , Receptor de Morte Celular Programada 1/genética , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/imunologia , Glioma/patologia , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
7.
Sci Rep ; 7(1): 1217, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28450700

RESUMO

In this study, we evaluated the consequences of reducing Galectin-1 (Gal-1) in the tumor micro-environment (TME) of glioblastoma multiforme (GBM), via nose-to-brain transport. Gal-1 is overexpressed in GBM and drives chemo- and immunotherapy resistance. To promote nose-to-brain transport, we designed siRNA targeting Gal-1 (siGal-1) loaded chitosan nanoparticles that silence Gal-1 in the TME. Intranasal siGal-1 delivery induces a remarkable switch in the TME composition, with reduced myeloid suppressor cells and regulatory T cells, and increased CD4+ and CD8+ T cells. Gal-1 knock-down reduces macrophages' polarization switch from M1 (pro-inflammatory) to M2 (anti-inflammatory) during GBM progression. These changes are accompanied by normalization of the tumor vasculature and increased survival for tumor bearing mice. The combination of siGal-1 treatment with temozolomide or immunotherapy (dendritic cell vaccination and PD-1 blocking) displays synergistic effects, increasing the survival of tumor bearing mice. Moreover, we could confirm the role of Gal-1 on lymphocytes in GBM patients by matching the Gal-1 expression and their T cell signatures. These findings indicate that intranasal siGal-1 nanoparticle delivery could be a valuable adjuvant treatment to increase the efficiency of immune-checkpoint blockade and chemotherapy.


Assuntos
Tratamento Farmacológico/métodos , Galectina 1/genética , Técnicas de Silenciamento de Genes , Glioblastoma/terapia , Imunoterapia/métodos , RNA Interferente Pequeno/administração & dosagem , Microambiente Tumoral/fisiologia , Administração Intranasal , Animais , Modelos Animais de Doenças , Camundongos , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
8.
Cell Death Differ ; 24(5): 832-843, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28234357

RESUMO

Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H2O2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.


Assuntos
Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Quimiocina CXCL1/genética , Quimiocinas CC/genética , Neutrófilos/imunologia , Animais , Animais Geneticamente Modificados , Apoptose , Linhagem Celular Tumoral , Quimiocina CCL2/imunologia , Quimiocina CXCL1/imunologia , Quimiocina CXCL10/imunologia , Quimiocinas CC/imunologia , Técnicas de Cocultura , Citotoxicidade Imunológica , Células Epiteliais/imunologia , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Melanócitos/imunologia , Melanócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neuroglia/imunologia , Neuroglia/patologia , Neutrófilos/citologia , Transdução de Sinais , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Peixe-Zebra
9.
J Neurooncol ; 132(2): 255-266, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28110411

RESUMO

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Serviços de Informação , Cooperação Internacional , Imagem por Ressonância Magnética , Sistema de Registros , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Ponte/diagnóstico por imagem , Adulto Jovem
10.
J Natl Cancer Inst ; 109(7)2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982754

RESUMO

Central nervous system-directed prophylactic chemotherapy increases survival in childhood leukemia, but possible late neurocognitive sequelae remain a concern. We compared intellectual performance (WAIS IV), memory (AVLT), and executive functioning (ANT) between adult leukemia survivors (n = 31) and control individuals (n = 35). In survivors, cerebrospinal fluid (CSF) levels of phosphorylated Tau (p-Tau) during treatment and total intrathecal methotrexate dose correlated with adult intellectual performance (Pearson's and Spearman's coefficients, respectively). Long-term memory and attentional control, both maturing before survivors' mean age at diagnosis, were unaffected (P > .05 on all four subtests), in contrast to cognitive flexibility and information processing (P < .05 for eight of the subtests), which mature during adolescence. CSF p-Tau and methotrexate dose negatively correlated with intellectual performance (r = -0.414, P = .04 and r = -0.484, P = .007, respectively), but not with each other (r = 0.219, P = .29). These data identify CSF p-Tau as a predictor of late neurocognitive sequelae (in addition to methotrexate dose). Early identification of children at risk could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Transtornos Cognitivos/líquido cefalorraquidiano , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Fosforilação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Sobreviventes , Adulto Jovem
11.
Cytotherapy ; 18(9): 1178-86, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27421737

RESUMO

BACKGROUND AIMS: Atypical rhabdoid/teratoid tumors (AT/RT) are the most common brain tumors in infants and associated with a dismal prognosis. Although intensification of first-line therapy has resulted in improvement of overall survival, novel treatment strategies are needed. Because immunotherapy has resulted in remarkable results in several adult tumor entities, incorporation of immunotherapy into AT/RT treatment offers a novel alternative. METHODS: We retrospectively analyzed data from 7 AT/RT patients from five countries treated within the HGG-Immuno Consortium. Two patients were ≤1 year and 4 patients were ≤2 years of age at diagnosis. All received immunotherapy with autologous, tumor-lysate-loaded dendritic cells (DCs) on a compassionate use basis using a schedule of three to four weekly DC vaccinations with up to 2 × 10(7) DCs per vaccine, followed by three lysate boosts each 1 month apart. RESULTS: Monocyte collections (median age at apheresis 31.5, range 20-143 months) and vaccinations were uneventful without any severe adverse event related to the vaccine, demonstrating feasibility and safety in this very young age group. Two children received immunotherapy during their primary and the remaining five during second- or third-line therapy. Three of seven patients survived long term with a follow-up of 143, 138 and 46 months, with at least two of them harboring somatic mutations. One long-term survivor was vaccinated during primary treatment and the other two after first or second relapse/progression. Two analyzed patients showed positive CD8(+) T-cell responses after vaccination. DISCUSSION: Our data demonstrate that anti-tumor immunotherapy with autologous DCs is feasible and safe in young children with ATRTs and that this approach warrants further investigation in controlled clinical trials.


Assuntos
Neoplasias Encefálicas/terapia , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Tumor Rabdoide/terapia , Neoplasias Encefálicas/imunologia , Criança , Pré-Escolar , Ensaios de Uso Compassivo , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Humanos , Lactente , Masculino , Monitorização Imunológica/métodos , Prognóstico , Estudos Retrospectivos , Tumor Rabdoide/imunologia , Inquéritos e Questionários , Resultado do Tratamento
12.
Stem Cells Transl Med ; 5(12): 1607-1619, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27465071

RESUMO

: MultiStem cells are clinical-grade multipotent adult bone marrow-derived progenitor cells (MAPCs), with extensive replication potential and broader differentiation capacity compared with mesenchymal stem cells. Human MAPCs suppress T-cell proliferation induced by alloantigens and mutually interact with allogeneic natural killer cells. In this study, the interaction between MultiStem and CD8+ cytotoxic T lymphocytes (CTLs) was addressed for the first time. In an in vitro setting, the immunogenicity of MultiStem, the susceptibility of MultiStem toward CTL-mediated lysis, and its effects on CTL function were investigated. MultiStem was nonimmunogenic for alloreactive CTL induction and was-even after major histocompatibility complex class I upregulation-insensitive to alloantigen-specific CTL-mediated lysis. Furthermore, MultiStem reduced CTL proliferation and significantly decreased perforin expression during the T-cell activation phase. As a consequence, MultiStem dose-dependently impaired the induction of CTL function. These effects of MultiStem were mediated predominantly through contact-dependent mechanisms. Moreover, MultiStem cells considerably influenced the expression of T-cell activation markers CD25, CD69, and human leukocyte antigen-DR. The MultiStem-induced CD8-CD69+ T-cell population displayed a suppressive effect on the induction of CTL function during a subsequent mixed-lymphocyte culture. Finally, the killer activity of activated antigen-specific CTLs during their cytolytic effector phase was also diminished in the presence of MultiStem. This study confirms that these clinical-grade MAPCs are an immune-modulating population that inhibits CTL activation and effector responses and are, consequently, a highly valuable cell population for adoptive immunosuppressive therapy in diseases where damage is induced by CTLs. SIGNIFICANCE: Because multipotent adult progenitor cells (MAPCs) are among the noteworthy adult mesenchymal stem cell populations for immune therapy and have the advantage over mesenchymal stem cells (MSCs) of large-scale manufacturing and banking potential and thus prompt availability, it is important to understand how MAPCs interact with immune cells to validate their widespread therapeutic applicability. Cytotoxic immune effector cells play a crucial role in immune homeostasis and in the pathogenesis of some autoimmune diseases. This study assessed for the first time the in vitro influence of a clinical-grade human MAPC product (MultiStem) on the cytotoxic function of CD8+ T cells (CTLs) by evaluating the immunogenicity of MAPCs and the susceptibility of MAPCs toward CTL-mediated lysis and by analyzing the mechanism of MAPC-mediated modulation of CTL functionality. These results may represent a highly relevant contribution to the current knowledge and, in combination with the results of future phase II/III trials using MultiStem, could lead to an intriguing continuation of stem cell-based research for immunotherapy.


Assuntos
Células-Tronco Adultas/citologia , Células-Tronco Multipotentes/citologia , Linfócitos T Citotóxicos/citologia , Adulto , Células-Tronco Adultas/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Biomarcadores/metabolismo , Comunicação Celular , Proliferação de Células , Citotoxicidade Imunológica , Galectina 1/metabolismo , Humanos , Isoantígenos/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Células-Tronco Multipotentes/metabolismo , Perforina/metabolismo , Linfócitos T Citotóxicos/metabolismo
13.
J Immunol ; 197(2): 533-40, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27288533

RESUMO

Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígeno B7-1/antagonistas & inibidores , Antígeno B7-1/imunologia , Antígenos CD28/antagonistas & inibidores , Antígenos CD28/imunologia , Antígenos CD40/antagonistas & inibidores , Antígenos CD40/imunologia , Ligante de CD40/antagonistas & inibidores , Ligante de CD40/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Imunossupressão , Camundongos
14.
Methods Mol Biol ; 1428: 277-83, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27236806

RESUMO

The immune system is a crucial player in the development of cancer. Once it is in imbalance and immunosuppressive mechanisms supporting tumor growth take over control, dendritic cell immunotherapy might offer a solution to restore the balance. There are several methods to manufacture dendritic cells but none of them has yet proven to be superior to others. In this chapter, we discuss the methodology using electroporation of mRNA encoding Wilms' tumor gene 1, survivin, and TriMix (mixture of caTLR4, CD40L, and CD70) to simultaneously load and mature dendritic cells.


Assuntos
Antígenos de Neoplasias/imunologia , Células Dendríticas/imunologia , Eletroporação/métodos , RNA Mensageiro/imunologia , Antígenos de Neoplasias/genética , Ligante CD27/genética , Ligante CD27/imunologia , Ligante de CD40/genética , Ligante de CD40/imunologia , Células Cultivadas , Células Dendríticas/citologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/imunologia , RNA Mensageiro/genética , Survivina , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Proteínas WT1/genética , Proteínas WT1/imunologia
15.
Oncoimmunology ; 5(2): e1083669, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27057467

RESUMO

Dendritic cell (DC)-based immunotherapy has yielded promising results against high-grade glioma (HGG). However, the efficacy of DC vaccines is abated by HGG-induced immunosuppression and lack of attention toward the immunogenicity of the tumor lysate/cells used for pulsing DCs. A literature analysis of DC vaccination clinical trials in HGG patients delineated the following two most predominantly applied methods for tumor lysate preparation: freeze-thaw (FT)-induced necrosis or FT-necrosis followed by X-ray irradiation. However, from the available clinical evidence, it is unclear which of both methodologies has superior immunogenic potential. Using an orthotopic HGG murine model (GL261-C57BL/6), we observed that prophylactic vaccination with DCs pulsed with irradiated FT-necrotic cells (compared to FT-necrotic cells only) prolonged overall survival by increasing tumor rejection in glioma-challenged mice. This was associated, both in prophylactic and curative vaccination setups, with an increase in brain-infiltrating Th1 cells and cytotoxic T lymphocytes (CTL), paralleled by a reduced accumulation of regulatory T cells, tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC). Further analysis showed that irradiation treatment of FT-necrotic cells considerably increased the levels of carbonylated proteins - a surrogate-marker of oxidation-associated molecular patterns (OAMPs). Through further application of antioxidants and hydrogen peroxide, we found a striking correlation between the amount of lysate-associated protein carbonylation/OAMPs and DC vaccine-mediated tumor rejection capacity thereby suggesting for the first time a role for protein carbonylation/OAMPs in at least partially mediating antitumor immunity. Together, these data strongly advocate the use of protein oxidation-inducing modalities like irradiation for increasing the immunogenicity of tumor lysate/cells used for pulsing DC vaccines.

16.
Sci Transl Med ; 8(328): 328ra27, 2016 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-26936504

RESUMO

The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (T(H)1) immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce T(H)1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In a curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to T(H)1/cytotoxic T lymphocyte/T(H)17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of T(H)1/cytotoxic T lymphocyte/T(H)17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment.


Assuntos
Neoplasias Encefálicas/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Glioma/imunologia , Linfócitos T Citotóxicos/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linfócitos T CD8-Positivos/imunologia , Morte Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Gradação de Tumores , Perileno/análogos & derivados , Perileno/farmacologia , Perileno/uso terapêutico , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Citotóxicos/efeitos dos fármacos
17.
J Control Release ; 227: 71-81, 2016 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-26902800

RESUMO

Galectin-1 (Gal-1) is a naturally occurring galactose-binding lectin, which is overexpressed in glioblastoma multiforme (GBM). Gal-1 is associated with tumor progression, and is a potent immune suppressor in the tumor micro-environment. To inhibit Gal-1 in GBM, an effective therapy is required that reaches the central nervous system tumor, with limited systemic effects. In this study, we report for the first time that concentrated chitosan nanoparticle suspensions can deliver small interfering RNA (siRNA) into the central nervous system tumor within hours after intranasal administration. These nanoparticles are able to complex siRNA targeting Gal-1 to a high percentage, and protect them from RNAse degradation. Moreover, a successful intracellular delivery of anti-Gal-1 siRNA resulted in a decreased expression of Gal-1 in both murine and human GBM cells. Sequence specific RNAinterference, resulted in more than 50% Gal-1 reduction in tumor bearing mice. This study indicates that the intranasal pathway is an underexplored transport route for delivering siRNA-based therapies targeting Gal-1 in the treatment of GBM.


Assuntos
Neoplasias Encefálicas/terapia , Encéfalo/patologia , Quitosana/química , Galectina 1/genética , Glioblastoma/terapia , Nanopartículas/química , RNA Interferente Pequeno/administração & dosagem , Administração Intranasal , Animais , Encéfalo/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos
18.
Pediatr Blood Cancer ; 63(3): 486-92, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26586230

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease, frequently affecting young children. PROCEDURE: We performed a retrospective study in patients younger than 16 years old manifesting with skin symptoms, and documented their different cutaneous lesions and systemic symptoms. We compared subgroups of children with single-system, skin-only, and multisystem disease and sought signs predictive for multisystem disease. In a small sample of patients, BRAF mutations were analyzed in archived biopsies. RESULTS: A wide spectrum of cutaneous presentations varying from crusted nodules and papules, blisters, vascular tumor-like lesions, scaling orange to red macules (frequently in seborrheic regions) to purpuric macules, and papules was documented in our cohort of 32 children. Otitis externa was a common manifestation and mucosal lesions were seen in three patients. A novel manifestation was a red-blue nodule that appeared in a patient after a vaccination. None of the cutaneous lesions was predictive for the classification or final outcome as a single-system or multisystem disease. However, later onset and a more protracted course of skin lesions were more frequent findings in multisystem LCH. Mucosal lesions and otitis externa were almost exclusively seen in patients with multisystem disease, a finding that warrants further investigation. Both wild-type (WT) and mutated BRAF were found not only in multisystem LCH, but also in skin-only LCH. Two cases with rapidly resolving congenital lesions had WT BRAF. CONCLUSIONS: Late onset and a protracted course of skin lesions are associated with MS-LCH, whereas WT BRAF is found in rapidly resolving skin lesions.


Assuntos
Histiocitose de Células de Langerhans/patologia , Pele/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos
19.
Front Immunol ; 6: 588, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26635802

RESUMO

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

20.
Biomed Res Int ; 2015: 842923, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26413548

RESUMO

PURPOSE: We have focused on finding a classifier that best discriminates between tumour progression and regression based on multiparametric MR data retrieved from follow-up GBM patients. MATERIALS AND METHODS: Multiparametric MR data consisting of conventional and advanced MRI (perfusion, diffusion, and spectroscopy) were acquired from 29 GBM patients treated with adjuvant therapy after surgery over a period of several months. A 27-feature vector was built for each time point, although not all features could be obtained at all time points due to missing data or quality issues. We tested classifiers using LOPO method on complete and imputed data. We measure the performance by computing BER for each time point and wBER for all time points. RESULTS: If we train random forests, LogitBoost, or RobustBoost on data with complete features, we can differentiate between tumour progression and regression with 100% accuracy, one time point (i.e., about 1 month) earlier than the date when doctors had put a label (progressive or responsive) according to established radiological criteria. We obtain the same result when training the same classifiers solely on complete perfusion data. CONCLUSIONS: Our findings suggest that ensemble classifiers (i.e., random forests and boost classifiers) show promising results in predicting tumour progression earlier than established radiological criteria and should be further investigated.


Assuntos
Glioblastoma , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Algoritmos , Estudos de Coortes , Glioblastoma/diagnóstico , Glioblastoma/epidemiologia , Glioblastoma/patologia , Humanos , Recidiva Local de Neoplasia
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