Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade.

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation.

mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors.

Background: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines.

CXCL9 recombinant adeno-associated virus (AAV) virotherapy sensitizes glioblastoma (GBM) to anti-PD-1 immune checkpoint blockade.

The promise of immunotherapy to induce long-term durable responses in conventionally treatment resistant tumors like glioblastoma (GBM) has given hope for patients with a dismal prognosis. Yet, few patients have demonstrated a significant survival benefit despite multiple clinical trials designed to invigorate immune recognition and tumor eradication. Insights gathered over the last two decades have revealed numerous mechanisms by which glioma cells resist conventional therapy and evade immunological detection, underscoring the need for strategic combinatorial treatments as necessary to achieve appreciable therapeutic effects.

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases.

Purpose: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain.

The current landscape of immunotherapy for pediatric brain tumors.

Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.

Tracking adoptive T cell immunotherapy using magnetic particle imaging.

Adoptive cellular therapy (ACT) is a potent strategy to boost the immune response against cancer. ACT is effective against blood cancers but faces challenges in treating solid tumors. A critical step for the success of ACT immunotherapy is to achieve efficient trafficking and persistence of T cells to solid tumors.

HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells.

Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown.

Adult precision medicine: learning from the past to enhance the future.

Despite therapeutic advances for other malignancies, gliomas remain challenging solid tumors to treat. Complete surgical resection is nearly impossible due to gliomas' diffuse infiltrative nature, and treatment is hampered by restricted access to the tumors due to limited transport across the blood-brain barrier. Recent advances in genomic studies and next-generation sequencing techniques have led to a better understanding of gliomas and identification of potential aberrant signaling pathways.

RNA-electroporated T cells for cancer immunotherapy.

Adoptive T cell therapy has proven effective against hematologic malignancies and demonstrated efficacy against a variety of solid tumors in preclinical studies and clinical trials. Nonetheless, antitumor responses against solid tumors remain modest, highlighting the need to enhance the effectiveness of this therapy. Genetic modification of T cells with RNA has been explored to enhance T-cell antigen specificity, effector function, and migration to tumor sites, thereby potentiating antitumor immunity.

Glioma cell proliferation is enhanced in the presence of tumor-derived cilia vesicles.

Background: The mechanisms by which primary cilia affect glioma pathogenesis are unclear. Depending on the glioma cell line, primary cilia can promote or inhibit tumor development. Here, we used piggyBac-mediated transgenesis to generate patient-derived glioblastoma (GBM) cell lines that stably express Arl13b:GFP in their cilia.

Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma.

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast-cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow-cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions.

Immunotherapy for Brain Tumors.

Despite aggressive surgery, radiation, and systemic chemotherapy, the prognosis for patients diagnosed with malignant brain tumors remains extremely poor, and standard treatments carry significant risks for long-term neurocognitive deficits. There is a clear and urgent need for the development of more effective treatments that will add minimal toxicity to standard therapies for invasive brain cancers. Cancer immunotherapy is a treatment modality that holds promise for the delivery of tumor-specific cytotoxicity, with the potential to eliminate brain tumor cells without harming the eloquent brain.

PCM1 Depletion Inhibits Glioblastoma Cell Ciliogenesis and Increases Cell Death and Sensitivity to Temozolomide.

A better understanding of the molecules implicated in the growth and survival of glioblastoma (GBM) cells and their response to temozolomide (TMZ), the standard-of-care chemotherapeutic agent, is necessary for the development of new therapies that would improve the outcome of current GBM treatments. In this study, we characterize the role of pericentriolar material 1 (PCM1), a component of centriolar satellites surrounding centrosomes, in GBM cell proliferation and sensitivity to genotoxic agents such as TMZ. We show that PCM1 is expressed around centrioles and ciliary basal bodies in patient GBM biopsies and derived cell lines and that its localization is dynamic throughout the cell cycle.

Neonatal seizures induced by pentylenetetrazol or kainic acid disrupt primary cilia growth on developing mouse cortical neurons.

Neonatal or early-life seizures (ELS) are often associated with life-long neurophysiological, cognitive and behavioral deficits, but the underlying mechanisms contributing to these deficits remain poorly understood. Newborn, post-migratory cortical neurons sprout ciliary buds (procilia) that mature into primary cilia. Disruption of the growth or signaling capabilities of these cilia has been linked to atypical neurite outgrowth from neurons and abnormalities in neuronal circuitry.

Disruption of KIF3A in patient-derived glioblastoma cells: effects on ciliogenesis, hedgehog sensitivity, and tumorigenesis.

KIF3A, a component of the kinesin-2 motor, is necessary for the progression of diverse tumor types. This is partly due to its role in regulating ciliogenesis and cell responsiveness to sonic hedgehog (SHH). Notably, primary cilia have been detected in human glioblastoma multiforme (GBM) tumor biopsies and derived cell lines.

Detection of primary cilia in human glioblastoma.

Glioblastoma (GBM) is the most common malignant adult brain tumor and carries a poor prognosis due to primary and acquired resistance. While many cellular features of GBM have been documented, it is unclear if cells within these tumors extend a primary cilium, an organelle whose associated signaling pathways may regulate proliferation, migration, and survival of neural precursor and tumor cells. Using immunohistochemical and electron microscopy (EM) techniques, we screened human GBM tumor biopsies and primary cell lines for cilia.

Enzymatic digestion improves the purity of harvested cerebral microvessels.

The harvest of intact cerebral microvessel yields could permit the in vitro characterization of mechanisms that underlie numerous vascular-linked central nervous system (CNS) phenomena. Here, we test (1) the effect of mild enzyme digestion on microvessel purity and yield; and then (2) the effect of variable centrifugation and filtration methods on microvessel yields. The brains of female Sprague-Dawley rats (4 weeks-old; n=38) were removed rapidly and homogenized.