Publications by authors named "Jessica B Foster"

Diffuse intrinsic pontine glioma (DIPG) is a fatal central nervous system (CNS) tumor that confers a median survival of 11 months. As B7-H3 is expressed on pediatric CNS tumors, we conducted BrainChild-03, a single-center, dose-escalation phase 1 clinical trial of repetitive intracerebroventricular (ICV) dosing of B7-H3-targeting chimeric antigen receptor T cells (B7-H3 CAR T cells) for children with recurrent or refractory CNS tumors and DIPG. Here we report results from Arm C, restricted to patients with DIPG.

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Article Synopsis
  • Pediatric low-grade gliomas (pLGGs) show varying treatment responses and poor outcomes when complete tumor removal isn't possible, making early treatment prediction important.
  • A radiogenomic analysis combining MRI and RNA sequencing reveals three immune clusters in pLGGs, with one cluster having higher immune activity but worse prognosis, suggesting they might benefit from immunotherapy.
  • A developed radiomic signature accurately predicts these immune profiles and progression-free survival, identifying high-risk patients for potential targeted therapies.
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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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Pediatric brain cancer is the leading cause of disease-related mortality in children, and many aggressive tumors still lack effective treatment strategies. We characterized aberrant alternative splicing across pediatric brain tumors, identifying pediatric high-grade gliomas (HGGs) among the most heterogeneous. Annotating these events with UniProt, we identified 11,940 splice events in 5,368 genes leading to potential protein function changes.

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Purpose: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy.

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Purpose Of Review: Given the invasive and high-risk nature of brain surgery, the need for non-invasive biomarkers obtained from the peripheral blood is greatest in tumors of the central nervous system (CNS). In this comprehensive review, we highlight recent advances in blood biomarker development for adult and pediatric brain tumors.

Recent Findings: We summarize recent blood biomarker development for CNS tumors across multiple key analytes, including peripheral blood mononuclear cells, cell-free DNA, cell-free RNA, proteomics, circulating tumor cells, and tumor-educated platelets.

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Article Synopsis
  • 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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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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Diffuse leptomeningeal glioneuronal tumor (DLGNT) occurs predominantly in children and is typically characterized by diffuse leptomeningeal lesions throughout the neuroaxis with focal segments of parenchymal involvement. Recent reports have identified cases without diffuse leptomeningeal involvement that retain classic glioneuronal features on histology. In this report, we present a case of a 4-year-old boy with a large cystic-solid intramedullary spinal cord lesion that on surgical biopsy revealed a biphasic astrocytic tumor with sparsely distributed eosinophilic granular bodies and Rosenthal fibers.

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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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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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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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Background: Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.

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Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. She was treated with MEK inhibition with complete resolution of symptoms, near-complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system.

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Background Aims: Manufacturing of potent chimeric antigen receptor (CAR) T cells requires phenotypically naive and early memory T cells. We hypothesized lymphatic fluid collected from the thoracic duct of children would serve as a unique reservoir for early T cells, which could then be used for CAR T-cell therapy.

Methods: We evaluated lymphatic fluid collected from 25 pediatric patients undergoing thoracic duct cannulation for other clinical indications.

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(partner and localizer of BRCA2) gene encodes a protein that colocalizes with in nuclear foci and likely permits the stable intranuclear localization and accumulation of plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease mechanism. Biallelic pathogenic variants have been described in autosomal recessive Fanconi anemia.

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The field of cancer immunotherapy has progressed at an accelerated rate over the past decade. Pediatric brain tumors thus far have presented a formidable challenge for immunotherapy development, given their typically low mutational burden, location behind the blood-brain barrier in a unique tumor microenvironment, and intratumoral heterogeneity. Despite these challenges, recent developments in the field have resulted in exciting preclinical evidence for various immunotherapies and multiple clinical trials.

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Adoptive T cell therapy is a form of cellular therapy that utilizes human immune cells, often empowered by the expression of recombinant proteins, to attack selected targets present on tumor or infected cells. T cell-based immunotherapy has been progressing over the past several decades, and reached a milestone with the recent US Food and Drug Administration (FDA) approval of chimeric antigen receptor T cell therapy for relapsed and refractory leukemia and lymphoma. Although most studies have used viral vectors, a growing number of researchers have come to appreciate in vitro-transcribed (IVT) mRNA for the development, testing, and application of T cell-based immunotherapeutics.

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T cells made with messenger RNA (mRNA) encoding chimeric antigen receptor (CAR) offer a safe alternative to those transduced with viral CARs by mitigating the side effects of constitutively active T cells. Previous studies have shown that mRNA CAR T cells are transiently effective but lack persistence and potency across tumor types. It was hypothesized that the efficacy of mRNA CARs could be improved by utilizing recent advancements in RNA technology, such as incorporating a modified nucleoside, 1-methylpseudouridine, into the mRNA and applying a novel purification method using RNase III to eliminate dsRNA contaminants.

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Purpose Of Review: Immunotherapy for the treatment of cancer has advanced at a tremendous pace over the last decade. In this review, we provide an overview of recent progress in immunotherapy for the treatment of leukemia, focusing on antibody-drug conjugates (ADC), bi-specific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells.

Recent Findings: Ongoing clinical trials of CAR T cells directed against CD19 have produced complete remission rates as high as 93%, prompting global multicenter phase 2 trials and the first FDA approval of a CAR T-cell therapy.

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Introduction: Proteasome inhibitors have garnered interest as novel chemotherapeutic agents based on their ability to inhibit the growth of cancer cells by altering the balance of intracellular proteins. Initial clinical trials of this drug class focused on bortezomib, a reversible inhibitor of the 20S proteasome, with promising results for the treatment of adult hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma.

Areas Covered: This article will review the use of bortezomib and other proteasome inhibitors in both adult and pediatric populations, with a focus on their use in pediatrics.

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