Biology subjects

Gumin, J.

Publications and source records attributed to Gumin, J..

6 recordsLinked to original sources

bioRxiv2026

MRI-Trackable Mesenchymal Stem Cells for Oncolytic Therapy: A Clinically Feasible Dual-Labeling Protocol

Non-invasive imaging of oncolytic virus-loaded mesenchymal stem cells (MSCs) could help evaluate cell trafficking and delivery in cancer therapy. Labeling MSCs with iron oxide particles (IOPs) enables in vivo tracking using magnetic resonance imaging (MRI). This study evaluated a dual-labeling strategy that loads MSCs with MegaPro IOPs and the oncolytic virus Delta-24-RGD (DNX-2401; tasadenoturev) and assessed cellular function and MRI detectability. MSCs were labeled with IOPs alone or in combination with the oncolytic virus. We compared cell viability and intracellular iron content among IOP-labeled, dual-labeled, and naive MSCs, and evaluated differentiation, invasion, and immunophenotype in naive and IOP-labeled MSCs. We evaluated phantoms containing varying numbers of IOP-labeled MSCs (9 x 103-1.5 x 105 cells) using R2-, R2*-, and R1-weighted MRI, and generated corresponding relaxation rate maps to assess concentration dependent contrast and detection sensitivity. Iron content was comparable between IOP-labeled and dual-labeled MSCs (9.2 {+/-} 2.6 and 11.6 {+/-} 1.4 pg/cell, respectively), with >91% viability across all groups. IOP-labeled MSCs retained invasion and differentiation potential. At the highest labeled-cell concentration, R2*, R2, and R1 increased approximately 4, 2.5, and 1.5 fold, respectively, relative to the agarose control. The estimated detection limits were approximately 2 x 103 cells for R2* and 6 x 103 cells for R2 and R1. These findings demonstrate that dual labeling of MSCs with IOPs and oncolytic virus preserves key cellular characteristics while providing MRI-detectable contrast, supporting further investigation of this approach for image-guided tracking of cell-based cancer therapies.

bioengineering↗

bioRxiv2023

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice

BACKGROUNDOncolytic adenoviruses, such as Delta-24-RGD, show promise as a potential breakthrough in treating patients with high-grade gliomas. However, their effectiveness against gliomas can be hindered by the presence of neutralizing antibodies. METHODSProduction of human neutralizing antibodies against adenoviruses was assessed in two cohorts of patients with malignant gliomas treated with Delta-24-RGD in a phase 1 clinical trial. Sera containing neutralizing antibodies were also obtained from mice immunized with intramuscular injections of wild-type Ad5. Chimeric adenovirus was constructed using molecular cloning, and its activity was assessed in vitro using quantitative PCR, western blot, and transmission electron microscopy. The therapeutic efficacy of the chimeric virus was tested in vivo using sera from patients previously treated with Delta-24-RGD and immunocompetent murine models of glioma. RESULTSExamination of sera from patients with malignant gliomas treated with Delta-24-RGD revealed that in the cohort treated with multiple injections of this oncolytic adenovirus, a higher percentage of patients developed neutralizing antibodies when compared to the patients treated with a single injection of Delta-24-RGD. Of note, long-term survival was only observed in patients who received a single injection. Delta-24-RGD-H43m, a chimeric oncolytic adenovirus engineered to overcome virus neutralization, demonstrated a potent anti-glioma effect both in vitro and in vivo. This chimeric virus showed resilience against anti-Ad5 neutralizing antibodies and conferred better therapeutic efficacy compared to Delta-24-RGD in mice with immunity against Ad5. Of further clinical relevance, Delta-24-RGD-H43m also evaded the inhibitory effects of sera from human patients treated with Delta-24-RGD. CONCLUSIONSThe development of neutralizing antibodies due to multiple virus injections was associated with lower frequency of long-term survivors in a clinical trial. The new chimeric virus shows increased resilience to inactivation by the sera of human patients compared to the parental virus. These findings lay the foundation for a novel oncolytic virus treatment approach targeting a significant percentage of glioma patients with prior exposure to adenovirus.

cancer biology↗

bioRxiv2022

Immune Contexture of Isocitrate Dehydrogenase stratified Human Gliomas

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but only a limited view of a highly complex glioma associated immune contexture across isocitrate dehydrogenase mutation (IDH) classified gliomas is known. Herein, we present an unprecedentedly comprehensive view of myeloid and lymphoid cell type diversity based on our single cell RNA sequencing and spectral cytometry-based interrogation of tumor-associated leukocytes from fifty-five IDH stratified primary and recurrent human gliomas and three non-glioma brains. Our analyses revealed twenty-two myeloid and lymphoid cell types within and across glioma subtypes. Glioma severity correlated with microglial attrition concomitant with a continuum of invading monocyte-derived microglia-like and macrophages amongst other infiltrating conventional T and NK lymphocytes and unconventional mucosa associated invariant T (MAIT) cells. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). Furthermore, we identified phagocytosis and antigen presentation gene modules enriched in Triggering receptor expressed on myeloid (TREM)-2+ cells as a putative anti-glioma axis. Accelerated glioma growth was observed in Trem2 deficient mice implanted with CT2A glioma cells affirming the anti-glioma role of TREM2+ myeloid cells. In addition to providing a comprehensive landscape of glioma-specific immune contexture, our investigations discover TREM2 as a novel immunotherapy target for brain malignancies.

immunology↗

bioRxiv2021

Measuring the metabolic evolution of glioblastoma throughout tumor development, regression, and recurrence with hyperpolarized magnetic resonance

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. Hyperpolarized MRI detected significant changes of metabolism throughout tumor progression whereas conventional MRI was less sensitive. This was accompanied by aberrations in amino acid and phospholipid lipid metabolism and MCT1 expression. Hyperpolarized MRI can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.

biophysics↗

bioRxiv2020

Medium-chain acyl-CoA dehydrogenase, a gatekeeper of mitochondrial function in glioblastoma multiforme

Glioblastoma (GBM) is among the deadliest of human cancers. Despite extensive efforts, it has proven to be highly resistant to chemo- and immune-based therapeutic strategies, and little headway has been made with targeted inhibitors. Like many cancers, metabolism is dysregulated in GBM. Thus, to identify new vulnerabilities and drug targets in GBM, we conducted genetic screens using pooled RNAi libraries targeting metabolic enzymes. We screened multiple glioma stem cell-derived (GSC) xenograft models, which revealed that several enzymes involved in the mitochondrial metabolism of fatty acids were required for tumor cell proliferation. From among these, we focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids, due to its consistently high score across all of our screens, as well as its high expression level in multiple GSC models and its upregulation in GBM compared to normal brain. In this manuscript, we describe the dependence of GBM on sustained fatty acid metabolism to actively catabolize lipid species that would otherwise damage the mitochondrial structure. The uptake of mediumchain fatty acids lacks negative feedback regulation; therefore, in the absence of MCAD, medium-chain fatty acids accumulate to toxic levels, inducing reactive oxygen species (ROS), mitochondrial damage and failure, and apoptosis. Taken together, our findings uncover a previously unappreciated protective role exerted by MCAD in GBM cells, making it a unique and therapeutically exploitable vulnerability.

cancer biology↗

bioRxiv2020

Inhibition of the av integrin-TGF-b axis improves natural killer cell function against glioblastoma stem cells

Glioblastoma, the most aggressive brain cancer, often recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. Here, we show that patient-derived GSCs, but not normal astrocytes, are highly sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. In contrast, single cell analysis of autologous, tissue infiltrating NK cells isolated from surgical samples of high-grade glioblastoma patient tumors using mass cytometry and single cell RNA sequencing revealed an abnormal phenotype associated with impaired lytic function compared with peripheral blood NK cells from GBM patients or healthy donors. This immunosuppression was attributed to an integrin-TGF-{beta} mechanism, activated by direct cell-cell contact between GSCs and NK cells. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-{beta} signaling, or with TGF-{beta} receptor 2 gene-edited NK cells prevented GSC-induced NK cell dysfunction and tumor growth. Collectively, our findings reveal a novel mechanism of NK cell immune evasion by GSCs and implicate the integrin-TGF-{beta} axis as a useful therapeutic target to eliminate GSCs in this devastating tumor.

immunology↗