A5033949023- Glioma Diagnosis and Treatment
- Ultrasound and Hyperthermia Applications
- Metal complexes synthesis and properties
- Click Chemistry and Applications
- Radiopharmaceutical Chemistry and Applications
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Immune cells in cancer
- CAR-T cell therapy research
- Nanoplatforms for cancer theranostics
- Brain Metastases and Treatment
- Photoacoustic and Ultrasonic Imaging
- Cancer, Hypoxia, and Metabolism
- Nanoparticle-Based Drug Delivery
- Ferroptosis and cancer prognosis
- Neuroinflammation and Neurodegeneration Mechanisms
- Electron Spin Resonance Studies
- interferon and immune responses
- Medical Imaging Techniques and Applications
- Mathematical Biology Tumor Growth
- Immune Cell Function and Interaction
- Lanthanide and Transition Metal Complexes
- Sarcoma Diagnosis and Treatment
- Cell Adhesion Molecules Research
- Melanoma and MAPK Pathways
Northwestern University
2019-2025
Northwestern Medicine
2021-2025
Neurological Surgery
2019-2025
Midwestern University
2024-2025
Universidad Nacional Autónoma de México
2018-2024
Northwestern University
2024
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
2021-2024
Ultramet (United States)
2023
Instituto Nacional de Cancerología
2017-2021
University of Minnesota
2021
Introduction The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression IL15 one attractive strategy modulate TME. However, at present, it unclear if could be used directly target myeloid-derived suppressor (MDSCs), cellular component GBM Here, we explored MDSC express IL15Rα and feasibility exploiting its as an immunotherapeutic target. Methods RNA-seq, RT-qPCR, flow...
Abstract Given the marginal penetration of most drugs across blood-brain barrier, efficacy various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open barrier increase concentration liposomal doxorubicin PD-1 blocking antibodies (aPD-1). We report results on a cohort 4 GBM patients preclinical models treated with this approach. LIPU/MB increases by 2-fold 3.9-fold in human murine brains...
Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across blood-brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts BBB allowing for improved drug delivery brain. We investigated distribution, toxicity, and efficacy LIPU two different formulations paclitaxel, albumin-bound paclitaxel (ABX) dissolved cremophor (CrEL-PTX), preclinical models.The biodistribution ABX CrEL-PTX were compared without delivery....
Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With goal exploring ways to boost anti-GBM immunity, we developed a B cell–based vaccine (BVax) that consists 4-1BBL+ cells activated with CD40 agonism and IFNγ stimulation. BVax migrates key secondary lymphoid organs is proficient at antigen cross-presentation, which promotes both survival functionality CD8+ T cells. A combination...
Whereas the contribution of tumor microenvironment to profound immune suppression glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance CD8 T cell mediated killing are less understood. Kinases potentially druggable targets drive progression and might influence response. Here, we perform an in vivo CRISPR screen identify glioma kinases contribute evasion cells from recognition. The reveals checkpoint kinase 2 (Chek2) be most important contributing escape T-cell...
Introduction Glioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid play a pivotal role in shaping GBM microenvironment and influencing immune responses, with direct interactions effector critically impacting these processes. Methods Our study investigates CXCR6/CXCL16 axis T-cell tissues. We examined surface...
Abstract Background Glioblastoma is a highly aggressive brain cancer that resistant to conventional immunotherapy strategies. Botensilimab, an Fc-enhanced anti-CTLA-4 antibody (FcE-aCTLA-4), has shown durable activity in “cold” and immunotherapy-refractory cancers. Methods We evaluated the efficacy immune microenvironment phenotype of mouse analogue FcE-aCTLA-4 treatment-refractory preclinical models glioblastoma, both as monotherapy combination with doxorubicin delivered via low-intensity...
Abstract Purpose: We recently reported on clinical trials for patients with recurrent glioblastoma where low-intensity pulsed ultrasound and microbubbles (LIPU/MB) improved paclitaxel or carboplatin delivery into the brain. Here, we report variable local tumor control at maximal/target dose in our phase I trial (NCT04528680). To address this, investigated combination of preclinical glioma models. Experimental Design: performed MRI-based analysis to evaluate disease from trial. studied...
Abstract Purpose: Cancer immunoediting shapes tumor progression by the selection of cell variants that can evade immune recognition. Given evasion and intratumor heterogeneity characteristic gliomas, we hypothesized CD8+ T cells mediate in these tumors. Experimental Design: We developed retrovirus-induced PDGF+Pten−/− murine gliomas evaluated glioma immunogenicity absence depleting this population. Furthermore, characterized genomic alterations present presence cells. Results: Upon...
Understanding the spatial relationship and functional interaction of immune cells in glioblastoma (GBM) is critical for developing new therapeutics that overcome highly immunosuppressive tumor microenvironment. Our study showed B T form clusters within GBM microenvironment a 15-μm radius, suggesting could synapses GBM. However, GBM-infiltrating suppress activation CD8 + cells. To this immunosuppression, we leveraged B-cell functions by activating them with CD40 agonism, IFNγ, BAFF to...
Glioblastoma (GBM) is a highly aggressive and malignant brain tumor with limited therapeutic options poor prognosis. Despite current treatments, the invasive nature of GBM often leads to recurrence. A promising alternative strategy harness potential immune system against cells. Our previous data showed that Bvax (B-cell-based vaccine) can induce responses in preclinical models GBM. In this study, we aim characterize antigenic reactivity BVax-derived antibodies evaluate their potential. We...
Abstract Background The blood-brain barrier (BBB) impedes the passage of most circulating drugs into brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens BBB, improving parenchymal drug penetration. Parenchymal permanence upon short-lived BBB opening is unknown. We compared temozolomide, carboplatin, and fluorescein, investigated effect LIPU/MB on concentration carboplatin fluorescein. Methods analyzed four patients who underwent intraoperative intravenous...
Although GBM's immunosuppressive environment is well known, the tumor's resistance to CD8+ T cell killing not fully understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as key driver of in mouse glioma through an vivo CRISPR screen and demonstrated that Chk2 inhibition, combined with PD-1/PD-L1 blockade, significantly enhanced cell-mediated tumor improved survival preclinical model. Here, we aimed elucidate function Chek2. Immunoprecipitation (IP) followed by mass...
Abstract While chimeric antigen receptor (CAR) T-cell therapies present novel therapeutic opportunities, their clinical success has been limited when targeting malignant brain tumors, such as gliomas. Marked antigenic heterogeneity of those tumors underlies treatment resistance. Ultimately, it is crucial to promote endogenous T cell responses against tumor cells not targeted by the CAR (“epitope-spreading”). However, natural anatomical barriers and an immunosuppressive environment allow...
Abstract Although the immunosuppressive microenvironment of glioblastoma (GBM) is well-established, tumor-intrinsic mechanisms underlying resistance to CD8+ T cell-mediated killing remain incompletely understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as top contributor cell in GBM through an vivo CRISPR screen. Therapeutic evaluation demonstrated that Chek2 inhibition, combined with PD-1/PD-L1 immune checkpoint blockade, significantly enhanced tumor and improved survival...
ABSTRACT Background Immunotherapy has revolutionized cancer treatment but yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity driving immune checkpoint blockade efficacy. In glioblastoma (GBM), tumor B-cells are driven regulatory state that suppresses activation and T-cell function. Methods We used spatially resolved transcriptomics multiplex immunofluorescence characterize neighborhoods within GBM identify enhanced TGFβ-signaling...
BACKGROUND. Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not tumor microenvironment (TME), or analyzed via biopsies.
A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library 320 agents known to be blood-brain barrier permeable approved by the FDA, we interrogated breast metastasis vulnerabilities identify an effective agent. Metixene, antiparkinsonian drug, was identified as top therapeutic agent that capable decreasing cellular viability inducing cell death across different subtypes. This...