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Cardiovascular disease (CVD), a broad-spectrum term comprising coronary artery disease, stroke, hypertension, and heart failure, presents as one of the most significant strains on global healthcare systems. Coronary artery disease, caused by atherosclerosis, has various modifiable risk factors such as dietary changes and exercise. Since these risk factors are found to be linked to oxidative stress and inflammations, the dietary supplementation with vitamins' role in treating and preventing the diseases has been of much debate. With various vitamins having anti-inflammatory and antioxidative properties, studies have explored their correlation with cardiovascular health. Therefore, this narrative review explores and evaluates the benefits and risks of all vitamin supplementations in patients with CVD and provides future recommendations.
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Various preclinical studies have demonstrated that the success of immunotherapeutic strategies in inhibiting tumor progression in animal models of Glioblastoma multiforme (GBM). It is also evident that tumor-induced immune suppression drastically impacts the efficacy of immune based therapies. Among the mechanisms employed by GBM to induce immunosuppression is the accumulation of regulatory T cells (Tregs) and Myeloid derived suppressor cells (MDSCs). Advancing our understanding about the pathways regulating the expansion, accumulation and activity of MDSCs will allow for the development of therapies aimed at abolishing the inhibitory effect of these cells on immunotherapeutic approaches. In this review, we have focused on the origin, expansion and immunosuppressive mechanisms of MDSCs in animal models and human cancer, in particular GBM.
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Inmunoterapia/métodos , Células Mieloides/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/terapia , Microambiente Tumoral/inmunología , Animales , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T Reguladores/inmunologíaRESUMEN
Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.
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Terapia Genética , Glioma/genética , Glioma/inmunología , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Animales , Antígeno B7-H1/metabolismo , Biomarcadores , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Antígeno CTLA-4/metabolismo , Células Cultivadas , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Femenino , Expresión Génica , Terapia Genética/métodos , Glioma/patología , Glioma/terapia , Humanos , Inmunofenotipificación , Terapia de Inmunosupresión , Inmunoterapia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , TransgenesRESUMEN
Mechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here, we provide evidence that early-stage B cells in Eµ-myc mice are tumorigenic and sharply regress in the periphery between 41 and 65 days of age. Regression depended on CD4(+), CD8(+), NK1.1(+) cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, Eµ-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells.
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Proteínas de Ciclo Celular/fisiología , Proteínas de Unión al ADN/fisiología , Células Asesinas Naturales/fisiología , Leucemia de Células B/inmunología , Regresión Neoplásica Espontánea/genética , Regresión Neoplásica Espontánea/inmunología , Proteínas Serina-Treonina Quinasas/fisiología , Linfocitos T/fisiología , Proteínas Supresoras de Tumor/fisiología , Secuencia de Aminoácidos , Animales , Apoptosis/genética , Apoptosis/inmunología , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos/genética , Genes myc/fisiología , Cadenas mu de Inmunoglobulina/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/patología , Ratones , Ratones SCID , Ratones Transgénicos , Datos de Secuencia Molecular , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
NK cells play a crucial role in innate immunity against tumors. In many human tumors, Ras is chronically active, and tumor cells frequently express ligands for the activating NK cell receptor NKG2D. In this study, we report that Ras activation upregulates the expression of Raet1 protein family members Rae1α and Rae1ß in mouse and ULBP1-3 in human cells. In addition, Ras also induced MHC class I chain-related protein expression in some human cell lines. Overexpression of the constitutively active H-RasV12 mutant was sufficient to induce NKG2D ligand expression. H-RasV12-induced NKG2D ligand upregulation depended on Raf, MAPK/MEK, and PI3K, but not ATM or ATR, two PI3K-like kinases previously shown to induce NKG2D ligand expression. Analysis of the 5' untranslated regions of Raet1 family members suggested the presence of features known to impair translation initiation. Overexpression of the rate-limiting translation initiation factor eIF4E induced Rae1 and ULBP1 expression in a Ras- and PI3K-dependent manner. Upregulation of NKG2D ligands by H-RasV12 increased sensitivity of cells to NK cell-mediated cytotoxicity. In summary, our data suggest that chronic Ras activation is linked to innate immune responses, which may contribute to immune surveillance of H-Ras transformed cells.
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Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Neoplasias/inmunología , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Transducción de Señal/inmunología , Animales , Línea Celular Tumoral , Citotoxicidad Inmunológica/inmunología , Activación Enzimática , Humanos , Vigilancia Inmunológica/inmunología , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , TransfecciónRESUMEN
Two types of immunity, humoral and cellular, offer protection against COVID. Humoral protection, contributed by circulating neutralizing antibodies, can provide immediate protection but decays more quickly than cellular immunity and can lose effectiveness in the face of mutation and drift in the SARS-CoV-2 spike protein. Therefore, population-level seroprevalence surveys used to estimate population-level immunity may underestimate the degree to which a population is protected against COVID. In early 2021, before India began its vaccination campaign, we tested for humoral and cellular immunity to SARS-Cov-2 in representative samples of slum and non-slum populations in Bangalore, India. We found that 29.7% of samples (unweighted) had IgG antibodies to the spike protein and 15.5% had neutralizing antibodies, but at up to 46% showed evidence of cellular immunity. We also find that prevalence of cellular immunity is significantly higher in slums than in non-slums. These findings suggest (1) that a significantly larger proportion of the population in Bangalore, India, had cellular immunity to SARS-CoV-2 than had humoral immunity, as measured by serological surveys, and (2) that low socio-economic status communities display higher frequency of cellular immunity, likely because of greater exposure to infection due to population density.
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COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , India/epidemiología , COVID-19/epidemiología , Estudios Seroepidemiológicos , Inmunidad Celular , Anticuerpos Neutralizantes , Inmunidad Humoral , Anticuerpos Antivirales , VacunaciónRESUMEN
Mutant isocitrate-dehydrogenase 1 (mIDH1) synthesizes the oncometabolite 2-hydroxyglutarate (2HG), which elicits epigenetic reprogramming of the glioma cells' transcriptome by inhibiting DNA and histone demethylases. We show that the efficacy of immune-stimulatory gene therapy (TK/Flt3L) is enhanced in mIDH1 gliomas, due to the reprogramming of the myeloid cells' compartment infiltrating the tumor microenvironment (TME). We uncovered that the immature myeloid cells infiltrating the mIDH1 TME are mainly nonsuppressive neutrophils and preneutrophils. Myeloid cell reprogramming was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem/progenitor-like cells. Blocking G-CSF in mIDH1 gliomabearing mice restores the inhibitory potential of the tumor-infiltrating myeloid cells, accelerating tumor progression. We demonstrate that G-CSF reprograms bone marrow granulopoiesis, resulting in noninhibitory myeloid cells within mIDH1 glioma TME and enhancing the efficacy of immune-stimulatory gene therapy.
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Despite advances in uncovering the molecular mechanisms that mediate glioma progression and the implementation of novel therapeutic modalities, patients' prognosis remains dismal. This is due to both systemic and local tumor induced immune suppression. We are particularly interested in the role played by infiltrating immunosuppressive myeloid derived suppressor cells (MDSCs) in the glioma tumor microenvironment (TME). This immunosuppressive TME also interferes with the effectiveness of immunotherapies against glioma. Development of multipronged treatment approaches is imperative when aiming to generate a robust anti-glioma immune response. Evaluating the inhibitory potential of MDSCs within the TME is an important aspect for developing effective treatments for glioma. Herein, we discuss methodology to assess the inhibitory effects of MDSCs isolated from the TME using a mouse glioma model.
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Neoplasias Encefálicas/inmunología , Glioma/inmunología , Células Supresoras de Origen Mieloide/inmunología , Linfocitos T/inmunología , Microambiente Tumoral , Animales , Neoplasias Encefálicas/patología , Proliferación Celular , Separación Celular/métodos , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Glioma/patología , Tolerancia Inmunológica , Ratones , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/patología , Linfocitos T/patologíaRESUMEN
Diffuse Gliomas represent 80% of brain tumors with an average survival of the most aggressive form glioblastoma (GBM) 15-22 months from the time of diagnosis. The current standard of care includes tumor resection, chemotherapy and radiation, nevertheless, the incidence of recurrence remains high and there is a critical need for developing new therapeutic strategies. T-cell mediated immunotherapy that triggers an anti-tumor T cell-mediated memory response is a promising approach since it will not only attack the primary tumor but also prevent recurrence. Multiple immunotherapeutic strategies against glioma are currently being tested in clinical trials. We have developed an immune-mediated gene therapy (Thymidine kinase plus Fms-like tyrosine kinase 3 ligand: TK/Flt3L) which induces a robust anti-tumor T cell response leading to tumor regression, long-term survival and immunological memory in GBM models. Efficacy of the anti-glioma T cell therapy is determined by anti-tumor specific effector T cells. Therefore, assessing effector T cell activation status and function are critical readouts for determining the effectiveness of the therapy. Here, we detail methodologies to evaluate tumor specific T-cell responses using a genetically engineered Sleeping Beauty transposase-mediated glioma model. We first describe the glioma model and the generation of neurospheres (NS) that express the surrogate antigen cOVA. Then, we describe functional assays to determine anti-tumor T-cell response.
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Antígenos de Neoplasias , Neoplasias Encefálicas/terapia , Pruebas Inmunológicas de Citotoxicidad/métodos , Terapia Genética/métodos , Glioma/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Microambiente Tumoral/inmunología , Animales , Neoplasias Encefálicas/inmunología , Glioma/inmunología , Memoria Inmunológica , Inmunoterapia/métodos , Proteínas de la Membrana , Ratones , Linfocitos T/metabolismo , Timidina QuinasaRESUMEN
Glioblastoma multiforme (GBM) is an aggressive primary brain tumor, for which there is no cure. Treatment effectiveness for GBM has been limited due to tumor heterogeneity, an immunosuppressive tumor microenvironment (TME), and the presence of the blood-brain barrier, which hampers the transport of chemotherapeutic compounds to the central nervous system (CNS). High-density lipoprotein (HDL)-mimicking nanodiscs hold considerable promise to achieve delivery of bioactive compounds into tumors. Herein, we tested the ability of synthetic HDL nanodiscs to deliver chemotherapeutic agents to the GBM microenvironment and elicit tumor regression. To this end, we developed chemo-immunotherapy delivery vehicles based on sHDL nanodiscs loaded with CpG, a Toll-like receptor 9 (TLR9) agonist, together with docetaxel (DTX), a chemotherapeutic agent, for targeting GBM. Our data show that delivery of DTX-sHDL-CpG nanodiscs into the tumor mass elicited tumor regression and antitumor CD8+ T cell responses in the brain TME. We did not observe any overt off-target side effects. Furthermore, the combination of DTX-sHDL-CpG treatment with radiation (IR), which is the standard of care for GBM, resulted in tumor regression and long-term survival in 80% of GBM-bearing animals. Mice remained tumor-free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of anti-GBM immunological memory. Collectively, these data indicate that sHDL nanodiscs constitute an effective drug delivery platform for the treatment of GBM, resulting in tumor regression, long-term survival, and immunological memory when used in combination with IR. The proposed delivery platform has significant potential for clinical translation.
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Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Inmunoterapia/métodos , Lipoproteínas HDL/química , Lipoproteínas HDL/uso terapéutico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Docetaxel/química , Docetaxel/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Lomustina/química , Lomustina/uso terapéutico , Ratones , Modelos Biológicos , Paclitaxel/química , Paclitaxel/uso terapéutico , Ratas , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1R132H) are younger at diagnosis and live longer. IDH1 mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53 (TP53) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (ATRX). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1R132H mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1R132H, TP53 and ATRX inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1R132H in the context of TP53 and ATRX loss. We discovered that IDH1R132H expression in the genetic context of ATRX and TP53 gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1132H glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
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Daño del ADN/genética , Epigénesis Genética , Glioma/genética , Isocitrato Deshidrogenasa/genética , Mutación/genética , Proteínas Supresoras de Tumor/genética , Regulación hacia Arriba/genética , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Diferenciación Celular , Metilación de ADN/genética , Reparación del ADN/genética , Modelos Animales de Enfermedad , Ontología de Genes , Genoma , Glioma/patología , Histonas/metabolismo , Humanos , Ratones , Oligodendroglía/patología , Tolerancia a Radiación , Transducción de Señal , Análisis de SupervivenciaRESUMEN
PURPOSE: Cancer testis antigens are a group of tumor antigens with gene expression restricted to male germ cells in the testis and in various cancerous tissues. Recently, we reported a novel testis-specific sperm-associated antigen 9 (SPAG9) gene, a new member of the c-Jun NH(2)-terminal kinase-interacting protein family, having functional role in sperm-egg fusion and mitogen-activated protein kinase signaling pathway. National Center for Biotechnology Information Blast searches revealed SPAG9 nucleotide sequence similarities with expressed sequence tags of various cancerous tissues. In an effort to examine the clinical utility of SPAG9, we investigated the SPAG9 mRNA and protein expression in epithelial ovarian cancer (EOC). Humoral immune response to SPAG9 was also evaluated in EOC patients. EXPERIMENTAL DESIGN: We determined the expression profile of SPAG9 transcript by reverse transcription-PCR and RNA in situ hybridization and SPAG9 protein expression by immunohistochemistry in EOC specimens and human ovarian cancer cell lines. Using ELISA and Western blotting, we analyzed specific antibodies for SPAG9 in sera from patients with EOC. RESULTS: SPAG9 mRNA and protein expression was detected in 90% of EOC tissues and in all three human ovarian cancer cell lines. Specific SPAG9 antibodies were detected in 67% of EOC patients and not in sera from healthy individuals. CONCLUSIONS: Our findings indicate that SPAG9 is highly expressed in EOC and immunogenic in patients. Humoral immune response against SPAG9 in early stages of EOC suggests its important role in early diagnostics. These results collectively suggest that SPAG9, a novel member of cancer testis antigen family, could be a potential target for the development of diagnostic and therapeutic methods in EOC.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antígenos de Neoplasias/metabolismo , Inmunoterapia , Neoplasias Glandulares y Epiteliales/metabolismo , Neoplasias Ováricas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/inmunología , Anticuerpos Antineoplásicos/sangre , Antígenos de Neoplasias/inmunología , Biomarcadores de Tumor/análisis , Western Blotting , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Neoplasias Glandulares y Epiteliales/sangre , Neoplasias Glandulares y Epiteliales/inmunología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/inmunología , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Tumors are associated with expansion of immunosuppressive cells such as tumor associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). These cells promote tumor growth, angiogenesis, metastasis and immune escape. Cancer patients frequently present symptoms such as anemia, leukocytosis and/or cytopenia; associated with poor prognosis. To uncover tumor-mediated hematopoietic abnormalities and identify novel targets that can be harnessed to improve tumor-specific immune responses, we investigated the hematopoietic stem and progenitor cell compartment in melanoma bearing mice. We show that melanoma growth results in expansion of myeloid lineages such as MDSCs, macrophages and DCs along with a reduction in mature RBCs and platelets. Mature B lymphocytes in the blood and BM of melanoma mice were also reduced. Mice bearing melanoma showed extramedullary hematopoiesis in the spleen. Increased expansion of myeloid lineages occurred directly at the level of stem and progenitor cells. The reduction in mature B lymphocytes resulted from a block at the Pro-B cell stage in the bone marrow. Addition of recombinant IL-3 to bone marrow cells resulted in the expansion of committed myeloid progenitors including common myeloid precursors, granulocyte-monocyte precursors and megakaryocyte-erythrocyte precursors. In vivo, IL-3 receptor stimulation in melanoma bearing mice using an IL-3 antibody also resulted in a robust expansion of committed myeloid progenitors and hematopoietic stem cells. Collectively our findings demonstrate that tumor growth plays a pivotal role in reprogramming the host immune system by impacting hematopoiesis directly at the level of stem cell compartment.
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There is a large unmet need for effective therapeutic approaches for glioma, the most malignant brain tumor. Clinical and preclinical studies have enormously expanded our knowledge about the molecular aspects of this deadly disease and its interaction with the host immune system. In this review we highlight the wide array of immunotherapeutic interventions that are currently being tested in glioma patients. Given the molecular heterogeneity, tumor immunoediting and the profound immunosuppression that characterize glioma, it has become clear that combinatorial approaches targeting multiple pathways tailored to the genetic signature of the tumor will be required in order to achieve optimal therapeutic efficacy.
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Neoplasias Encefálicas/terapia , Glioma/terapia , Inmunoterapia/métodos , Encéfalo/inmunología , Neoplasias Encefálicas/inmunología , Glioma/inmunología , Humanos , Inmunoterapia/tendenciasRESUMEN
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival of 16.2-21.2 months post diagnosis (Stupp et al., N Engl J Med 352(10): 987-996, 2005). Because of its location, complete surgical resection is impossible; additionally because GBM is also resistant to chemotherapeutic and radiotherapy approaches, development of novel therapies is urgently needed. In this chapter we describe the development of preclinical animal models and a conditionally cytotoxic and immune-stimulatory gene therapy strategy that successfully causes tumor regression in several rodent GBM models.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Animales , Línea Celular Tumoral , Terapia Genética , Humanos , Ratones , Neoplasias Experimentales , RatasRESUMEN
INTRODUCTION: Outcome for glioma (GBM) remains dismal despite advances in therapeutic interventions including chemotherapy, radiotherapy and surgical resection. The overall survival benefit observed with immunotherapies in cancers such as melanoma and prostate cancer has fuelled research into evaluating immunotherapies for GBM. AREAS COVERED: Preclinical studies have brought a wealth of information for improving the prognosis of GBM and multiple clinical studies are evaluating a wide array of immunotherapies for GBM patients. This review highlights advances in the development of immunotherapeutic approaches. We discuss the strategies and outcomes of active and passive immunotherapies for GBM including vaccination strategies, gene therapy, check point blockade and adoptive T cell therapies. We also focus on immunoediting and tumor neoantigens that can impact the efficacy of immunotherapies. EXPERT OPINION: Encouraging results have been observed with immunotherapeutic strategies; some clinical trials are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of GBM and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature.
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Glioblastoma/inmunología , Glioblastoma/terapia , Glioma/inmunología , Glioma/terapia , Inmunoterapia/tendencias , Animales , Predicción , Terapia Genética/métodos , Terapia Genética/tendencias , Glioblastoma/diagnóstico , Glioma/diagnóstico , Humanos , Inmunización Pasiva/métodos , Inmunización Pasiva/tendencias , Inmunoterapia/métodos , Pronóstico , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and showed that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single-nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs nonhomologous end joining and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival.
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Neoplasias Encefálicas/patología , Reparación del ADN por Unión de Extremidades , ADN Helicasas/deficiencia , Glioma/patología , Proteínas Nucleares/deficiencia , Animales , Neoplasias Encefálicas/genética , Proliferación Celular , Cromosomas de los Mamíferos/genética , Variaciones en el Número de Copia de ADN/genética , Daño del ADN , ADN Helicasas/genética , ADN Helicasas/metabolismo , Modelos Animales de Enfermedad , Glioma/genética , Humanos , Ratones , Inestabilidad de Microsatélites , Mutación/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleótido Simple/genética , Análisis de Supervivencia , Homeostasis del Telómero , Transposasas/metabolismo , Proteína Nuclear Ligada al Cromosoma XRESUMEN
In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints.
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Neoplasias del Sistema Nervioso Central/inmunología , Neoplasias del Sistema Nervioso Central/terapia , Glioblastoma/inmunología , Glioblastoma/terapia , Tolerancia Inmunológica , Memoria Inmunológica , Inmunoterapia/métodos , Ensayos Clínicos como Asunto , Humanos , Medicina de Precisión , Nivel de Atención , Insuficiencia del TratamientoRESUMEN
The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8(+) T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV-treated GL26 tumor-bearing mice, associated with an increase in the frequency of tumor-specific and IFNγ(+) CD8(+) T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8(+) T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8(+) T cells within the tumor and IFNγ release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM.
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Glioma/inmunología , Glioma/metabolismo , Memoria Inmunológica , Inmunoterapia , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Adenoviridae/genética , Animales , Antígenos/inmunología , Antígenos de Superficie/metabolismo , Línea Celular Tumoral , Citocinas/biosíntesis , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Ganciclovir/farmacología , Terapia Genética , Vectores Genéticos/genética , Glioblastoma/inmunología , Glioblastoma/metabolismo , Glioblastoma/terapia , Glioma/mortalidad , Glioma/terapia , Inmunofenotipificación , Proteínas de la Membrana/genética , Ratones , Ratas , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Citotóxicos/inmunología , Timidina Quinasa/genéticaRESUMEN
INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad)-mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED: This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION: The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM.