Publications by authors named "Joy Gumin"

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.

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Background: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear.

Methods: In this study, we used sequential single-cell transcriptomics on 144 678 and spectral cytometry on over 2 million immune cells encompassing 48 human gliomas to decipher their immune landscape.

Results: We identified 22 distinct immune cell types that contribute to glioma immunity.

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Given recent advances in the delivery of novel antitumor therapeutics using endovascular selective intraarterial delivery methods in neuro-oncology, there is an urgent need to develop methods for intracarotid injections in mouse models, including methods to repair the carotid artery in mice after injection to allow for subsequent injections. We developed a method of intracarotid injection in a mouse model to deliver therapeutics into the internal carotid artery (ICA) with two alternative procedures. During injection, the needle is inserted into the common carotid artery (CCA) after tying a suture around the external carotid artery (ECA) and injected therapeutics are delivered into the ICA.

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Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain.

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Background: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation.

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Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

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Article Synopsis
  • Researchers developed a rabbit model to study endovascular selective intra-arterial (ESIA) infusions for treating glioblastoma using human GBM cell lines to implant tumors.
  • The model involved immunosuppressing rabbits and performing microcatheter infusions of mesenchymal stem cells loaded with an oncolytic adenovirus (MSC-D24), demonstrating the approach's safety and efficacy.
  • Results showed successful tumor formation in the rabbits and that the MSC-D24 treatment effectively targeted the implanted tumors, providing a relevant method for testing new cancer therapies.
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  • Glioblastoma stem cell-like cells (GSCs) are crucial for the growth and resistance of glioblastoma (GBM), and long noncoding RNAs (lncRNAs) play a significant but under-researched role in this context.
  • A study identified a specific lncRNA that, when depleted, reduces the proliferation and self-renewal of GSCs, leading to longer survival in GBM models and increased sensitivity to radiation therapy.
  • The research also revealed that this lncRNA interacts with YBX1 to stabilize mRNA of key regulators, creating a loop that promotes GSC malignancy and suggests that targeting the lncRNA/YBX1 axis could enhance GBM treatments.
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  • The study investigates how the oncolytic adenovirus Delta-24-RGDOX can enhance the effectiveness of adoptive cell therapies, especially in treating solid tumors where cancer cells can be diverse and the surrounding environment suppresses immune responses.
  • Using mouse models with B16 melanoma, the researchers found that administering Delta-24-RGDOX after injecting tumor-associated antigen (TAA)-targeting T cells led to improved tumor responses and increased survival rates.
  • This approach not only activated the tumor microenvironment but also boosted the immune response by increasing the density of specific immune cells, ultimately enhancing systemic antitumor immunity and reducing the chances of tumor relapse.
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  • Improved glioblastoma (GBM) therapies are needed, with a focus on evaluating LSD1 inhibitors in models that reflect patient tumor diversity and resistance.
  • Researchers conducted RNA-seq to explore the effects of LSD1 knockdown and inhibition in patient-derived GBM stem cell lines and mouse models, leading to the identification of genes related to treatment resistance.
  • Findings suggest that LSD1 inhibitors can delay tumor growth, and identifying resistance-associated genes may help develop more effective combination treatments in the future.
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Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma.

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Treatment-resistant glioma stem cells are thought to propagate and drive growth of malignant gliomas, but their markers and our ability to target them specifically are not well understood. We demonstrate that podoplanin (PDPN) expression is an independent prognostic marker in gliomas across multiple independent patient cohorts comprising both high- and low-grade gliomas. Knockdown of PDPN radiosensitized glioma cell lines and glioma-stem-like cells (GSCs).

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Article Synopsis
  • * Researchers utilized various analysis methods, including RNA sequencing and flow cytometry, to assess the impact of the oncolytic virus Delta-24-RGDOX and its combination with IDO inhibitors in animal models of gliomas.
  • * Results indicated that the combination therapy led to increased CD8 T cell presence while reducing immunosuppressive cell populations, ultimately suggesting a strategy to boost the immune response against tumors.
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Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI could detect changes in tumor progression faster than conventional anatomic MRI in patient-derived glioblastoma murine models. To capture the dynamic nature of cancer metabolism, hyperpolarized MRI, NMR spectroscopy, and immunohistochemistry were performed at several time-points during tumor development, regression, and recurrence.

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Article Synopsis
  • The study investigates the use of bone marrow-derived human mesenchymal stem cells (BM-hMSCs) from glioma patients who have undergone marrow-toxic chemotherapy as carriers for an oncolytic virus called Delta-24-RGD, which targets and kills glioma cells.
  • Five patients with recurrent malignant glioma were enrolled, and their BM-hMSCs were cultured and shown to have similar properties to those from healthy donors, including the ability to differentiate into different cell types.
  • The findings indicate that the patient-derived BM-hMSCs effectively delivered Delta-24-RGD in preclinical models, significantly improving survival rates in mice with gliomas, suggesting potential for clinical application.
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Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor-infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors.

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  • Oncolytic adenoviruses show promise for treating solid tumors like glioblastoma (GBM), but existing animal models are limited due to species selectivity, necessitating a new approach.
  • Researchers developed an intracranial glioma model using Syrian hamsters that allows for viral replication and immune response assessment, addressing gaps in current models.
  • Findings revealed that the virus Delta-24-RGD effectively kills tumor cells, increases T-cell infiltration in tumors, and significantly improves survival in treated hamsters compared to controls, suggesting the model's potential for future clinical applications.
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Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism.

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Background: Fusion genes form as a result of abnormal chromosomal rearrangements linking previously separate genes into one transcript. The FGFR3-TACC3 fusion gene (F3-T3) has been shown to drive gliomagenesis in glioblastoma (GBM), a cancer that is notoriously resistant to therapy. However, successful targeting of F3-T3 via small molecular inhibitors has not revealed robust therapeutic responses, and specific targeting of F3-T3 has not been achieved heretofore.

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Background: Delta-24-RGD, an oncolytic adenovirus, shows promise against glioblastoma. To enhance virus delivery, we recently demonstrated that human bone marrow-derived mesenchymal stem cells loaded with Delta-24-RGD (hMSC-D24) can eradicate glioblastomas in mouse models. There are no studies examining the safety of endovascular selective intra-arterial (ESIA) infusions of MSC-D24 in large animals simulating human clinical situations.

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Background: Malignant gliomas continue to have a poor clinical outcome with available therapies. In the past few years, new targeted biologic therapies have been studied, with promising results. However, owing to problems with ineffective IV delivery of these newer agents, an alternative, more direct delivery mechanism is needed.

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Background: Viroimmunotherapy is evolving as a strong alternative for the standard treatment of malignant gliomas. Promising results from a recent clinical trial testing the anticancer effect of Delta-24-RGD in patients with glioblastoma suggested the induction of antitumoral immunity after viral administration. To further enhance the anti-glioma immune effect, we have armed Delta-24-RGD with the costimulatory ligand GITRL (Delta-24-GREAT [Glucocorticoid Receptor Enhanced Activity of T cells]).

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Objective: Bone marrow-derived human mesenchymal stem cells (BM-hMSCs) have been used in clinical trials for the treatment of several neurological disorders. MSCs have been explored as a delivery modality for targeted viral therapeutic agents in the treatment of intracranial pathologies. Delta-24-RGD, a tumor-selective oncolytic adenovirus designed to target malignant glioma cells, has been shown to be effective in animal models and in a recent clinical trial.

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Background: Glioblastoma (GBM) is a lethal, heterogeneous human brain tumor, with regulatory mechanisms that have yet to be fully characterized. Previous studies have indicated that the transcriptional repressor REST (repressor element-1 silencing transcription factor) regulates the oncogenic potential of GBM stem cells (GSCs) based on level of expression. However, how REST performs its regulatory role is not well understood.

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