RESUMEN
OBJECTIVE: Sonodynamic therapy (SDT) is gaining attention as a promising new noninvasive brain tumor treatment that targets and selectively kills tumor cells, with limited side effects. This review examines the mechanisms of SDT and ongoing clinical trials looking at optimization of sonication parameters for potential treatment of glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). The results in the first patient with recurrent GBM treated at the Mayo Clinic are briefly discussed. METHODS: The authors of this literature review used electronic databases including PubMed, EMBASE, and OVID. Articles reporting relevant preclinical and clinical trials were identified by searching for text words/phrases and MeSH terms, including the following: "sonodynamic therapy," "SDT," "focused ultrasound," "5-ALA," "ALA," "brain tumors," "diffuse pontine glioma," "glioblastoma," and "high grade glioma." RESULTS: Preclinical and clinical trials investigating the specific use of SDT in brain tumors were reviewed. In preclinical models of high-grade glioma and GBM, SDT has shown evidence of targeted tumor cell death via the production of reactive oxygen species. Emerging clinical trial results within recurrent GBM and DIPG show evidence of successful treatment response, with minimal side effects experienced by recruited patients. So far, SDT has been shown to be a promising noninvasive cancer treatment that is well tolerated by patients. The authors present pilot data suggesting good radiological response of GBM to a single SDT treatment, with unpublished observation of a lack of off-target effects even after multiple (monthly) sonication outpatient treatments. The scope of the clinical trials of SDT is to investigate whether it can be the means by which the fatal diagnosis of GBM or DIPG is converted into that of a chronic, treatable disease. CONCLUSIONS: SDT is safe, repeatable, and better tolerated than both chemotherapy and radiotherapy. It has been shown to have an effect in human cancer therapy, but more clinical trials are needed to establish standardized protocols for sonosensitizer delivery, treatment parameters, and combination therapies. The most appropriate timing of treatment also remains to be determined-whether to prevent recurrence in the postoperative period, or as a salvage option in patients with recurrent GBM for which redo surgery is inappropriate. It is hoped that SDT will also be developed for a wider spectrum of clinical indications, such as metastases, meningioma, and low-grade glioma. Further clinical trials are in preparation.
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Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/terapia , Terapia por Ultrasonido/métodos , Glioblastoma/terapia , Neoplasias del Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/terapiaRESUMEN
BACKGROUND: For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset. METHODS: Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups. RESULTS: Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044). CONCLUSION: We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.
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Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Glioblastoma , Irinotecán , Recurrencia Local de Neoplasia , Humanos , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Irinotecán/uso terapéutico , Masculino , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/mortalidad , Glioblastoma/terapia , Glioblastoma/patología , Persona de Mediana Edad , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidad , Temozolomida/uso terapéutico , Estimación de Kaplan-Meier , Estudios Retrospectivos , Quimioradioterapia , Bases de Datos FactualesRESUMEN
Glioblastoma (GBM) stands for the most common and aggressive type of brain tumour in adults. It is highly invasive, which explains its short rate of survival. Little is known about its risk factors, and current therapy is still ineffective. Hence, efforts are underway to develop novel and effective treatment approaches against this type of cancer. Exosomes are being explored as a promising strategy for conveying and delivering therapeutic cargo to GBM cells. They can fuse with the GBM cell membrane and, consequently, serve as delivery systems in this context. Due to their nanoscale size, exosomes can cross the blood-brain barrier (BBB), which constitutes a significant hurdle to most chemotherapeutic drugs used against GBM. They can subsequently inhibit oncogenes, activate tumour suppressor genes, induce immune responses, and control cell growth. However, despite representing a promising tool for the treatment of GBM, further research and clinical studies regarding exosome biology, engineering, and clinical applications still need to be completed. Here, we sought to review the application of exosomes in the treatment of GBM through an in-depth analysis of the scientific and clinical studies on the entire process, from the isolation and purification of exosomes to their design and transformation into anti-oncogenic drug delivery systems. Surface modification of exosomes to enhance BBB penetration and GBM-cell targeting is also a topic of discussion.
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Antineoplásicos , Barrera Hematoencefálica , Neoplasias Encefálicas , Sistemas de Liberación de Medicamentos , Exosomas , Glioblastoma , Exosomas/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Humanos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificaciónRESUMEN
INTRODUCTION: There are no guidelines or prospective studies defining the optimal surgical treatment for glioblastomas in older patients (≥70 years), for those with a limited functioning performance at presentation (Karnofsky Performance Scale ≤70) or for those with tumours in certain locations (midline, multifocal). Therefore, the decision between resection and biopsy is varied, among neurosurgeons internationally and at times even within an institution. This study aims to compare the effects of maximal tumour resection versus tissue biopsy on survival, functional, neurological and quality of life outcomes in these patient subgroups. Furthermore, it evaluates which modality would maximise the potential to undergo adjuvant treatment. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of an observational nature. Consecutive patients with glioblastoma will be treated with resection or biopsy and matched with a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients that have received adjuvant treatment with chemotherapy and radiotherapy. Secondary endpoints are (1) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months after surgery; (2) progression-free survival (PFS); (3) quality of life at 6 weeks, 3 months and 6 months after surgery and (4) frequency and severity of serious adverse events. The total duration of the study is 5 years. Patient inclusion is 4 years; follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media. TRIAL REGISTRATION NUMBER: NCT06146725.
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Neoplasias Encefálicas , Glioblastoma , Calidad de Vida , Humanos , Glioblastoma/cirugía , Glioblastoma/patología , Glioblastoma/terapia , Estudios Prospectivos , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Biopsia/métodos , Estudios Multicéntricos como Asunto , Procedimientos Neuroquirúrgicos/métodos , Anciano , Femenino , MasculinoRESUMEN
Inhibiting epigenetic modulators can transcriptionally reactivate transposable elements (TEs). These TE transcripts often generate unique peptides that can serve as immunogenic antigens for immunotherapy. Here, we ask whether TEs activated by epigenetic therapy could appreciably increase the antigen repertoire in glioblastoma, an aggressive brain cancer with low mutation and neoantigen burden. We treated patient-derived primary glioblastoma stem cell lines, an astrocyte cell line and primary fibroblast cell lines with epigenetic drugs, and identified treatment-induced, TE-derived transcripts that are preferentially expressed in cancer cells. We verified that these transcripts could produce human leukocyte antigen class I-presented antigens using liquid chromatography with tandem mass spectrometry pulldown experiments. Importantly, many TEs were also transcribed, even in proliferating nontumor cell lines, after epigenetic therapy, which suggests that targeted strategies like CRISPR-mediated activation could minimize potential side effects of activating unwanted genomic regions. The results highlight both the need for caution and the promise of future translational efforts in harnessing treatment-induced TE-derived antigens for targeted immunotherapy.
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Antígenos de Neoplasias , Neoplasias Encefálicas , Elementos Transponibles de ADN , Epigénesis Genética , Glioblastoma , Transcripción Genética , Glioblastoma/genética , Glioblastoma/terapia , Glioblastoma/inmunología , Humanos , Elementos Transponibles de ADN/genética , Línea Celular Tumoral , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Regulación Neoplásica de la Expresión Génica , Inmunoterapia/métodosRESUMEN
Despite unprecedented survival in patients with glioblastoma (GB), the aggressive primary brain cancer remains largely incurable and its mechanisms of treatment resistance have gained particular attention. The cytokine interleukin 6 (IL-6) and its receptor weave through the hallmarks of malignant gliomas and may represent a key vulnerability to GB. Known for activating the STAT3 pathway in autocrine fashion, IL-6 is amplified in GB and has been recognized as a negative biomarker for GB prognosis, rendering it a putative target of novel GB therapies. While it has been recognized as a biologically active component of GB for three decades only with concurrent advances in understanding of complementary immunotherapy has the concept of targeting IL-6 for a human clinical trial gained scientific footing.
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Neoplasias Encefálicas , Glioblastoma , Interleucina-6 , Glioblastoma/terapia , Humanos , Interleucina-6/metabolismo , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos , Receptores de Interleucina-6 , Factor de Transcripción STAT3/metabolismo , Inmunoterapia/métodosRESUMEN
BACKGROUND: Mutations of the TP53 oncosuppressor gene are frequent events in patients with malignant tumors including IDH-wildtype GBM (GBM IDH wt). However, the effective impact of TP53 mutations on prognosis has been poorly evaluated. METHODS: We performed a retrospective study investigating the impact of TP53 mutations on patients with GBM IDH wt. Only patients with PS=0-1, treated with temozolomide concurrent with and adjuvant to radiotherapy, and younger than 70 years assessed with NGS were included in the analysis. RESULTS: 97 GBM IDH wt have been selected. The median follow-up was 34.5 months (95â¯%CI, 30.6 - NA). Overall, 20 patients (19.4â¯%) presented a TP53 mutation. There were no significant differences in terms of TERT mutation (75â¯% vs 79.2â¯%) between TP53 mutated and TP53 wild-type (wt) patients. We detected 6 TP53 mutations not previously described within GBM IDH wt patients. The overall survival (OS) did not significantly differ between TP53 mutated and wt patients (HR 0.69, 95â¯%CI 0.37-1.27, p = 0.24). Considering only patients with an OS longer than 36 months (n = 10), the presence of a TP53 mutation was significantly associated with prolonged survival (45.6 months vs Not Reached, p = 0.037). CONCLUSION: The presence of a TP53 mutation does not appear to be correlated with overall survival in this patient cohort. While there is an association with survival for patients with an OS of 36 months or longer, the number of patients is low and there is no available evidence correlating TP53 mutations to long-term survivors.
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Neoplasias Encefálicas , Glioblastoma , Isocitrato Deshidrogenasa , Mutación , Proteína p53 Supresora de Tumor , Humanos , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/mortalidad , Glioblastoma/terapia , Masculino , Femenino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Persona de Mediana Edad , Isocitrato Deshidrogenasa/genética , Proteína p53 Supresora de Tumor/genética , Estudios Retrospectivos , Adulto , Anciano , PronósticoRESUMEN
Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.
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Neoplasias Encefálicas , Proteína delta de Unión al Potenciador CCAAT , Glioblastoma , Interleucinas , Células Asesinas Naturales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Glioblastoma/inmunología , Glioblastoma/genética , Glioblastoma/patología , Glioblastoma/terapia , Interleucinas/genética , Interleucinas/metabolismo , Interleucinas/inmunología , Humanos , Animales , Ratones , Proteína delta de Unión al Potenciador CCAAT/metabolismo , Proteína delta de Unión al Potenciador CCAAT/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Interleucina-15/genética , Interleucina-15/metabolismo , Interleucina-15/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).
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Glioblastoma , Receptores Quiméricos de Antígenos , Linfocitos T , Glioblastoma/terapia , Glioblastoma/inmunología , Humanos , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Inmunoterapia Adoptiva/métodos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
In this work the effect of combining ultrasound (US) hyperthermia (HT) with radiotherapy (RT) was investigated. The treatment was applied to a GBM xenograft nude mouse model obtained by injecting 2 × 10 6 U87 luc+ cells. The combined treatment group received 6 Gy and HT at 43 ∘ for 8 min. The ultrasound field was generated by a closed-loop computationally controlled system, consisting of a High Intensity Focused Ultrasound (HIFU) transducer with centre frequency 3.57 MHz, a power amplifier, a function generator and a MATLAB controller. A mechanical cone adaptor has been designed to use the HIFU beam at a pre-defined post-focal distance. Two thermocouples were placed between the mechanical cone and the mice skin to measure and control the temperature during the HT treatment. Radiotherapy was carried out by using a dedicated small animal image guided radiotherapy system. Measurements of tumor volume performed with a caliper showed good tumor control for the RT-HT group with respect to the RT or control groups for up to 21 days after treatment. The mean value of the normalized (before therapy) tumor volume was almost equal to 0.5 for two weeks after treatment with an increase to 1.5 at sacrifice. The control and HT groups showed a higher value of about 1.5 during the first two weeks and 3.5 at the end of the follow-up period. We concluded that the use of HT as a radiosensitizer can improve the outcome for glioblastoma treatments.
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Glioblastoma , Hipertermia Inducida , Ratones Desnudos , Animales , Glioblastoma/radioterapia , Glioblastoma/patología , Glioblastoma/terapia , Hipertermia Inducida/métodos , Ratones , Humanos , Terapia Combinada , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patología , Modelos Animales de Enfermedad , Carga Tumoral/efectos de la radiaciónRESUMEN
Rationale: Since oncogene expression products often exhibit upregulation or abnormally activated activity, developing a technique to regulate abnormal protein levels represent a viable approach for treating tumors and protein abnormality-related diseases. Methods: We first screened out eMIATAC components with high targeted degradation efficiency and explored the mechanism by which eMIATAC induced target protein degradation, and verified the degradation efficiency of the target protein by protein imprinting and flow cytometry. Next, we recombined eMIATAC with some controllable elements to verify the regulatable degradation performance of the target protein. Subsequently, we constructed eMIATAC that can express targeted degradation of AKT1 and verified its effect on GBM cell development in vitro and in vivo. Finally, we concatenated eMIATAC with CAR sequences to construct CAR-T cells with low BATF protein levels and verified the changes in their anti-tumor efficacy. Results: we developed a system based on the endosome-microautophagy-lysosome pathway for degrading endogenous proteins: endosome-MicroAutophagy TArgeting Chimera (eMIATAC), dependent on Vps4A instead of lysosomal-associated membrane protein 2A (LAMP2A) to bind to the chaperone Hsc70 and the protein of interest (POI). The complex was then transported to the lysosome by late endosomes, where degradation occurred similarly to microautophagy. The eMIATACs demonstrated accuracy, efficiency, reversibility, and controllability in degrading the target protein EGFP. Moreover, eMIATAC exhibited excellent performance in knocking down POI when targeting endogenous proteins in vivo and in vitro. Conclusions: The eMIATACs could not only directly knock down abnormal proteins for glioma treatment but also enhance the therapeutic effect of CAR-T cell therapy for tumors by knocking down T cell exhaustion-related proteins. The newly developed eMIATAC system holds promise as a novel tool for protein knockdown strategies. By enabling direct control over endogenous protein levels, eMIATAC has the potential to revolutionize treatment for cancer and genetic diseases.
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Autofagia , Endosomas , Inmunoterapia Adoptiva , Proteolisis , Humanos , Animales , Endosomas/metabolismo , Línea Celular Tumoral , Ratones , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/metabolismo , Glioblastoma/terapia , Glioblastoma/metabolismo , Glioblastoma/patología , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas del Choque Térmico HSC70/metabolismo , Lisosomas/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Adoptive T-cell therapy targeting antigens expressed in glioblastoma has emerged as a potential therapeutic strategy to prevent or delay recurrence and prolong overall survival in this aggressive disease setting. Ephrin receptor A3 (EphA3), which is highly expressed in glioblastoma; in particular, on the tumor vasculature and brain cancer stem cells, is an ideal target for immune-based therapies. METHODS: We have designed an EphA3-targeted chimeric antigen receptor (CAR) using the single chain variable fragment of a novel monoclonal antibody, and assessed its therapeutic potential against EphA3-expressing patient-derived glioblastoma neurospheres, organoids and xenografted glioblastoma tumors in immunodeficient mice. RESULTS: In vitro expanded EphA3 CAR T cells from healthy individuals efficiently recognize and kill EphA3-positive glioblastoma cells in vitro. Furthermore, these effector cells demonstrated curative efficacy in an orthotopic xenograft model of glioblastoma. EphA3 CAR T cells were equally effective in targeting patient-derived neurospheres and infiltrate, disaggregate, and induce apoptosis in glioblastoma-derived organoids. CONCLUSIONS: This study provides compelling evidence supporting the therapeutic potential of EphA3 CAR T-cell therapy against glioblastoma by targeting EphA3 associated with brain cancer stem cells and the tumor vasculature. The ability to target patient-derived glioblastoma underscores the translational significance of this EphA3 CAR T-cell therapy in the pursuit of effective and targeted glioblastoma treatment strategies.
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Glioblastoma , Receptor EphA3 , Glioblastoma/terapia , Glioblastoma/inmunología , Humanos , Animales , Ratones , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Inmunoterapia Adoptiva/métodos , Linfocitos T/inmunología , Línea Celular TumoralRESUMEN
Glioblastoma (GBM) is associated with a median survival rate of less than 15 months, necessitating innovative treatment approaches. This study investigates the safety and efficacy of the low-frequency magnetic field (LFMF) OM-100 instrument in GBM therapy. In vitro experiments utilized normal astrocyte and GBM cell lines, determining that OM-100 at 100 kHz for 72 h selectively targeted GBM cells without harming normal cells. Subsequent analyses revealed OM-100's impact on cell viability, apoptosis, migration, invasion, reactive oxide species levels, and PD-L1 expression. In vivo studies on mice with U87-induced GBM demonstrated OM-100's synergy with anti-PD-1 therapy, leading to significant tumor volume reduction and increased apoptosis. Notably, OM-100 exhibited safety in healthy mice. Overall, OM-100 could enhance anti-PD-1 immunotherapy effectiveness probably by directly inhibiting tumor proliferation and migration as well as promoting PD-L1 expression, offering a promising therapeutic strategy for GBM treatment.
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Proliferación Celular , Glioblastoma , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Glioblastoma/terapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glioblastoma/metabolismo , Animales , Ratones , Humanos , Línea Celular Tumoral , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inmunoterapia/métodos , Proliferación Celular/efectos de los fármacos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Magnetoterapia/métodos , Supervivencia Celular/efectos de los fármacosRESUMEN
Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.
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Neoplasias Encefálicas , Vacunas contra el Cáncer , Glioblastoma , Medicina de Precisión , Vacunas de Subunidades Proteicas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos de Neoplasias/inmunología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Glioblastoma/inmunología , Glioblastoma/terapia , Medicina de Precisión/métodos , Vacunas de Subunidades Proteicas/inmunología , Vacunas de Subunidades Proteicas/uso terapéutico , Linfocitos T/inmunología , Resultado del TratamientoRESUMEN
The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2-xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.
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5'-Nucleotidasa , Glioblastoma , Inmunoterapia , Glioblastoma/terapia , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/tratamiento farmacológico , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/antagonistas & inhibidores , Animales , Humanos , Ratones , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Cobre/química , Cobre/farmacología , Oro/química , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Nanopartículas del Metal/química , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/antagonistas & inhibidores , Adenosina/química , Adenosina/farmacologíaRESUMEN
Glioblastoma multiforme (GBM) is the most frequent primary brain malignancy in adults. Despite improvements in imaging and therapy, the prognosis remains poor. To evaluate and compare the impact of combining bevacizumab with temozolomide and radiotherapy on progression-free survival (PFS) and overall survival (OS) in patients diagnosed with GBM. A comprehensive search was conducted across multiple databases, including PubMed, Embase, Scopus, and The Cochrane Library, covering the period from their inception to December 2022. The collected data underwent analysis employing appropriate statistical methods. Six articles were included in this systematic review and meta-analysis. The addition of bevacizumab to the combination of temozolomide/radiotherapy did not increase the OS in GBM patients. The pooled odds ratio (OR) was 0.843 (95% CI: 0.615-1.156, P = 0.290). The addition of bevacizumab to radiotherapy/temozolomide did not increase the PFS in patients with GBM. The pooled OR was 0.829 (95% CI: 0.561-1.224, P = 0.346). The funnel plot demonstrated the absence of the alleged pleiotropic effects by showing no evidence of observable variability across the estimations. This study does not support the benefit of the addition of bevacizumab to temozolomide and radiotherapy in improving OS and PFS in GBM patients.
Asunto(s)
Bevacizumab , Neoplasias Encefálicas , Glioblastoma , Temozolomida , Glioblastoma/radioterapia , Glioblastoma/tratamiento farmacológico , Glioblastoma/terapia , Temozolomida/uso terapéutico , Humanos , Bevacizumab/uso terapéutico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidad , Antineoplásicos Alquilantes/uso terapéutico , Quimioradioterapia/métodos , Resultado del TratamientoRESUMEN
GBM is the most common, aggressive, and intracranial primary brain tumor; it originates from the glial progenitor cells, has poor overall survival (OS), and has limited treatment options. In this decade, GBM immunotherapy is in trend and preferred over several conventional therapies, due to their better patient survival outcome. This review explores the clinical trials of several immunotherapeutic approaches (immune checkpoint blockers (ICBs), CAR T-cell therapy, cancer vaccines, and adoptive cell therapy) with their efficacy and safety. Despite significant progress, several challenges (viz., immunosuppressive microenvironment, heterogeneity, and blood-brain barrier (BBB)) were experienced that hamper their immunotherapeutic potential. Furthermore, these challenges were clinically studied to be resolved by multiple combinatorial approaches, discussed in the later part of the review. Thus, this review suggests the clinical use and potential of immunotherapy in GBM and provides the holistic recent knowledge and future perspectives.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Inmunoterapia , Microambiente Tumoral , Humanos , Inmunoterapia/métodos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Glioblastoma/terapia , Glioblastoma/inmunología , Microambiente Tumoral/inmunología , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Animales , Barrera Hematoencefálica/inmunologíaRESUMEN
Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).
Asunto(s)
Neoplasias Encefálicas , Vacunas contra el Cáncer , Células Dendríticas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/inmunología , Glioblastoma/mortalidad , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Persona de Mediana Edad , Femenino , Masculino , Adulto , Anciano , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Temozolomida/uso terapéutico , Temozolomida/administración & dosificación , Supervivencia sin ProgresiónRESUMEN
In the past decades, the therapeutic effect of glioblastoma (GBM) has not been significantly improved. Generous evidence indicates that S100A9 has a wide range of functions in tumors, but its exploration in GBM is less. The purpose of this study is to conduct a comprehensive bioinformatics analysis and cytological experiment on S100A9 in GBM. The expression data and clinical data of GBM samples were downloaded from the public database, and comprehensive bioinformatics analysis was performed on S100A9 in GBM using R software. Wound healing assay and transwell assay were used to detect the migration activity of cells, and colony formation assay, EdU staining, and CCK-8 assay were used to detect the proliferation activity of cells. The effect of S100A9 on the migration activity of M2 macrophages was verified by the cell co-culture method. The protein expression was detected by western blotting and immunohistochemical staining. S100A9 is an independent prognostic factor in GBM patients and is related to poor prognosis. It can be used as an effective tool to predict the response of GBM patients to immune checkpoint inhibitors (ICIs). In addition, S100A9 can promote the malignant progression of GBM and the migration of M2 macrophages. On the whole, our study highlights the potential value of S100A9 in predicting prognosis and immunotherapeutic response in GBM patients. More importantly, S100A9 may promote the malignant progress of GBM by involving in some carcinogenic pathways and remodeling the tumor microenvironment (TME).
Asunto(s)
Neoplasias Encefálicas , Calgranulina B , Movimiento Celular , Glioblastoma , Inmunoterapia , Macrófagos , Humanos , Glioblastoma/inmunología , Glioblastoma/patología , Glioblastoma/terapia , Calgranulina B/metabolismo , Calgranulina B/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Pronóstico , Inmunoterapia/métodos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/inmunología , Línea Celular Tumoral , Progresión de la Enfermedad , Proliferación Celular , Biomarcadores de Tumor/metabolismo , Masculino , Femenino , Microambiente Tumoral/inmunología , Biología ComputacionalRESUMEN
Glioblastoma, a highly malignant intracranial tumor, has acquired slow progress in treatment. Previous clinical trials involving targeted therapy and immune checkpoint inhibitors have shown no significant benefits in treating glioblastoma. This ineffectiveness is largely due to the complex immunosuppressive environment of glioblastoma. Glioblastoma cells exhibit low immunogenicity and strong heterogeneity and the immune microenvironment is replete with inhibitory cytokines, numerous immunosuppressive cells, and insufficient effective T cells. Fortunately, recent Phase I clinical trials of CART therapy for glioblastoma have confirmed its safety, with a small subset of patients achieving survival benefits. However, CART therapy continues to face challenges, including blood-brain barrier obstruction, antigen loss, and an immunosuppressive tumor microenvironment (TME). This article provides a detailed examination of glioblastoma's immune microenvironment, both from intrinsic and extrinsic tumor cell factors, reviews current clinical and basic research on multi-targets CART treatment, and concludes by outlining the key challenges in using CART cells for glioblastoma therapy.