Publications by authors named "Nicholas Vitanza"

Article Synopsis
  • Liquid biopsy assays analyzing cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) show promise for monitoring pediatric CNS tumors, enhancing risk assessment and treatment personalization.
  • A pilot study demonstrated that low-pass whole genome sequencing (LP-WGS) on CSF samples from 17 patients could successfully analyze 94% of samples, detecting significant genetic variants in 90% of cases.
  • LP-WGS proved more sensitive than standard CSF cytological tests, identifying additional tumor markers, underscoring the need for larger studies to confirm its potential as a predictive biomarker.
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  • B7-H3 is a promising target for immunotherapy in pediatric solid tumors due to its limited presence in critical organs, leading to a phase I trial testing B7-H3 CAR T cells in young patients with tough-to-treat tumors.
  • Sixteen patients participated in the trial, with no serious dose-limiting toxicities from the first CAR T cell infusion, and one patient showed a partial response after a second infusion.
  • The study concluded that while B7-H3 CAR T cells were generally tolerable and had limited anti-tumor effects, a strong CAR T cell response may be needed for better outcomes, emphasizing the importance of the patient's immune environment.
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Central nervous system (CNS) tumors are the leading cause of cancer-related death in children. Typical therapy for CNS tumors in children involves a combination of surgery, radiation, and chemotherapy. While upfront therapy is effective for many high-grade tumors, therapy at the time of relapse remains limited.

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Background: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors.

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  • Artificial intelligence in medicine usually faces challenges related to small, non-diverse patient data due to privacy concerns, but federated learning (FL) offers a solution by allowing training across different hospitals without sharing sensitive data.
  • The newly developed FL-PedBrain platform is specifically designed for pediatric brain tumors, enabling collaborative training for tumor classification and segmentation across 19 international centers, addressing the lack of diverse datasets in this area.
  • FL-PedBrain shows impressive performance metrics, maintaining almost equivalent accuracy to centralized data training while significantly improving segmentation performance by 20 to 30% at external sites, and allows for the examination of data variability in real-world situations.
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Background: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma.

Methods: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2).

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  • Diffuse midline glioma (DMG), particularly DIPG, is a fatal brain tumor with no effective treatments, but recent studies identified PIK3CA and MTOR as promising targets for therapy.
  • The research demonstrates that combining the PI3K/Akt/mTOR inhibitor paxalisib with the antihyperglycemic drug metformin and the PKC inhibitor enzastaurin can enhance treatment efficacy and prolong survival in animal models.
  • Advanced techniques like spatial transcriptomics and ATAC-Seq were used to evaluate the effects on tumor biology, revealing significant changes that could support a clinically relevant combination therapy for DIPG.
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  • Constitutional mismatch repair deficiency (CMMRD) is a syndrome that increases the risk of high-grade gliomas in children, leading to poor outcomes and making treatment challenging.* -
  • This study evaluates the effectiveness of the histone deacetylase inhibitor, quisinostat, on a hypermutant pediatric high-grade glioma model, showing it causes significant tumor regression and alters gene expression.* -
  • The findings suggest quisinostat’s potential as a treatment option for hypermutant DIPG and indicate that loss of mismatch repair function may enhance sensitivity to this drug, encouraging further research on HDAC inhibitors for similar cancers.*
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Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules.

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While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition.

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Introduction: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity.

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Unlabelled: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9 to 11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

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Purpose Of Review: Correlative studies should leverage clinical trial frameworks to conduct biospecimen analyses that provide insight into the bioactivity of the intervention and facilitate iteration toward future trials that further improve patient outcomes. In pediatric cellular immunotherapy trials, correlative studies enable deeper understanding of T cell mobilization, durability of immune activation, patterns of toxicity, and early detection of treatment response. Here, we review the correlative science in adoptive cell therapy (ACT) for childhood central nervous system (CNS) tumors, with a focus on existing chimeric antigen receptor (CAR) and T cell receptor (TCR)-expressing T cell therapies.

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Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

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Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN).

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Pediatric CNS tumors are responsible for the majority of cancer-related deaths in children and have poor prognoses, despite advancements in chemotherapy and radiotherapy. As many tumors lack efficacious treatments, there is a crucial need to develop more promising therapeutic options, such as immunotherapies; the use of chimeric antigen receptor (CAR) T cell therapy directed against CNS tumors is of particular interest. Cell surface targets such as B7-H3, IL13RA2, and the disialoganglioside GD2 are highly expressed on the surface of several pediatric and adult CNS tumors, raising the opportunity to use CAR T cell therapy against these and other surface targets.

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Background: Adult and pediatric tumors display stark differences in their mutation spectra and chromosome alterations. Here, we attempted to identify common and unique gene dependencies and their associated biomarkers among adult and pediatric tumor isolates using functional genetic lethal screens and computational modeling.

Methods: We performed CRISRP-Cas9 lethality screens in two adult glioblastoma (GBM) tumor isolates and five pediatric brain tumor isolates representing atypical teratoid rhabdoid tumors (ATRT), diffuse intrinsic pontine glioma, GBM, and medulloblastoma.

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Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites.

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Background: ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201.

Methods: This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design.

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Article Synopsis
  • The study focuses on a novel treatment for diffuse intrinsic pontine glioma (DIPG), a deadly brainstem tumor, using B7-H3-targeted chimeric antigen receptor (CAR) T cells.
  • A phase I trial (BrainChild-03) was conducted with three DIPG patients, where they received 40 infusions of B7-H3 CAR T cells, showing no severe toxic effects.
  • Results indicated one patient experienced significant improvement, and there was evidence of local immune activation and persistent CAR T cells in the patients' cerebrospinal fluid (CSF), suggesting this treatment approach's potential effectiveness.
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Article Synopsis
  • Diffuse midline gliomas (DMG) are aggressive brain tumors with poor survival rates and an unclear mechanism of invasion, linked to increased levels of the ID1 protein due to specific genetic mutations.
  • The study involved extensive genetic analyses and experiments to evaluate the role of ID1 in tumor growth and invasion, including tests with the compound cannabidiol (CBD).
  • Findings indicate that high ID1 expression correlates with tumor characteristics and enhances migration, while targeting ID1 with CBD effectively reduces tumor cell growth and movement, suggesting a potential therapeutic strategy for treating DMG.
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Diffuse midline glioma (DMG), including those of the brainstem (diffuse intrinsic pontine glioma), are pediatric tumors of the central nervous system (CNS). Recognized as the most lethal of all childhood cancers, palliative radiotherapy remains the only proven treatment option, however, even for those that respond, survival is only temporarily extended. DMG harbor an immunologically "cold" tumor microenvironment (TME) with few infiltrating immune cells.

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Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified.

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Bifurcation of cellular fates, a critical process in development, requires histone 3 lysine 27 methylation (H3K27me3) marks propagated by the polycomb repressive complex 2 (PRC2). However, precise chromatin loci of functional H3K27me3 marks are not yet known. Here, we identify critical PRC2 functional sites at high resolution.

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Background: Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs.

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