Biology subjects

Foster, J. B.

Publications and source records attributed to Foster, J. B..

5 recordsLinked to original sources

bioRxiv2025

Lack of Reproducibility of Gulf War Illness-like Behavioral Effects in War-related Chemical Agents and Stressor Exposure Rat Models

Gulf War illness (GWI) is characterized by a range of neurological and neuropsychiatric symptoms, including chronic pain, fatigue, mood problems, and cognitive issues. The pathophysiology is associated with war-related environmental chemical exposure and psychological stress, which are known to disrupt glutamatergic synaptic structure and function. The goal of this study was to evaluate the efficacy of the investigational new drug LH-001, a candidate for enhancing tripartite glutamatergic synapses, in a rat model of GWI. We began by attempting to induce GWI-like phenotypes in rats using a previously published protocol involving exposure to specific chemical agents and mild stress. However, these efforts were unsuccessful, as the expected GWI symptoms were not observed. We then performed two protocol modifications--using more potent chemical exposures and higher stress levels--but were still unable to produce the desired phenotypes. Our results highlight significant issues with the reliability of current GWI rat models. A comparative analysis of other studies suggests that GWI-like behavioral effects, when induced in rats by chemical agents and stress, show a broader lack of reproducibility across different laboratories. This calls into question the robustness of current rat models for GWI and poses challenges for preclinical drug development.

neuroscience↗

bioRxiv2025

A Tonic Signaling Code Predicts CAR-T Cell Efficacy in Diffuse Midline Glioma

Diffuse midline glioma (DIPG/DMG) is a uniformly fatal pediatric brain tumor with no effective cure. Although CAR T-cell therapy shows promise, clinical outcomes remain inconsistent due to limited persistence and premature exhaustion. Reliable predictive biomarkers are lacking, and proposed exhaustion or stemness markers provide limited utility. Here, we systematically compare multiple CAR-T constructs targeting clinically-relevant antigen B7-H3 and identify antigen-independent CAR activation, or tonic signaling, as a key determinant of therapeutic performance. We find that B7-H3 CAR-T cells with restrained tonic signaling display superior tumor killing, persistence, and resistance to exhaustion, along with reduced CAR membrane clustering, in patient-derived DIPG models. Integrated multi-omics and single-cell profiling further reveal a CAR-T tonic signaling-associated gene signature that outperforms conventional exhaustion or stemness markers in predicting therapeutic efficacy across multiple clinical trials, including DIPG and other tumor types. Together, these findings define a mechanistic and predictive framework to guide CAR design and improve clinical outcomes.

cancer biology↗

bioRxiv2025

Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation. MethodsWe tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models. ResultsB7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DMG/DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (p<0.003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells significantly extended survival in multiple DIPG xenograft mouse models (p<0.05). ConclusionsB7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models. Importance of the studyDiffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor. While B7-H3 CAR T cells have shown tolerability and potential benefit in early trials, combinatorial regimens may be required for consistent cures against this aggressive disease. This study demonstrates that a preclinical therapeutic regimen of B7-H3 CAR T cells with ONC206, a second-generation imipridone, increases anti-tumor efficacy in vitro and in orthotopic DIPG mouse models. To our knowledge, this is the first study to evaluate ONC206 in combination with CAR T cells. Our findings provide a preclinical roadmap for evaluating small molecules with CAR T cells to interrogate both their combined benefit and the effect of small molecules on T cells themselves. This work offers a biologically-informed, clinically translatable strategy integrating small molecule therapeutics with CAR T cell therapy and support the development of multi-agent immunotherapy trials for children with DIPG and other high-grade brain and spinal cord tumors. Key PointsO_LIB7-H3 CAR T cells are cytotoxic against preclinical DMG models. C_LIO_LIONC206 causes metabolic apoptosis in preclinical DMG models. C_LIO_LIB7-H3 CAR T cells and ONC206 have combinatorial efficacy against DMG. C_LI

cancer biology↗

bioRxiv2024

The splicing modulator CLK1 is a candidate oncogenic dependency in pediatric high-grade gliomas

BackgroundPediatric brain tumors are the leading cause of disease-related mortality in children, yet many aggressive tumors lack effective therapies. RNA splicing is a hallmark of cancer, but it has not yet been systematically studied in pediatric brain tumors. MethodsWe analyzed 729 pediatric brain tumors spanning histologies and molecular subtypes to quantify differential tumor splicing. We developed the Splicing Burden Index (SBI) to enable cross-sample comparisons and performed hierarchical clustering of highly variable splice events to define splicing-informed tumor groups. These were integrated with clinical outcomes, pathway activity, and proteogenomic data. Recurrent splice events were prioritized for predicted functional impact, and in vitro perturbation studies were performed targeting the splicing kinase CDC-like kinase 1 (CLK1). ResultsSBI revealed substantial inter- and intra-histology heterogeneity. Clusters were enriched for histologies and molecular subtypes, several of which were independently associated with survival beyond histology and clinical covariates. Spliceosome pathway activity varied across clusters and was associated with worse survival, yet was not correlated with SBI, indicating distinct dimensions of splicing dysregulation. Functional prioritization identified a recurrent in CLK1 exon 4, required for canonical kinase activity. CLK1 exon 4 inclusion followed an oncofetal pattern and showed context-dependent associations with outcome distinct from total CLK1 expression. Pharmacologic inhibition and exon 4-specific perturbation of CLK1 reduced tumor cell viability and disrupted cancer-relevant splicing and transcriptional programs. ConclusionsThis study systematically characterizes splicing in pediatric brain tumors, identifies splicing-informed subgroups, and prioritizes CLK1 exon 4 as an oncofetal tumor-specific event, motivating further preclinical exploration. Key Points[bullet] Splicing analysis of 729 pediatric CNS tumors identifies splicing-defined clusters. [bullet]CLK1 exon 4 inclusion is widespread and developmentally regulated. [bullet]Exon-level CLK1 regulation shows context-dependent links to prognosis in aggressive CNS tumors.

genomics↗

bioRxiv2021

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors

Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Here we show that the cell surface oncoprotein glypican 2 (GPC2) is highly expressed on multiple lethal pediatric brain tumors, including medulloblastomas, embryonal tumors with multi-layered rosettes, other CNS embryonal tumors, as well as definable subsets of highly malignant gliomas. To target GPC2 on these pediatric brain tumors with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we developed four mRNA chimeric antigen receptor (CAR) T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment. First, we validated and prioritized these CARs using in vitro cytotoxicity and T cell degranulation assays with GPC2-expressing neuroblastoma cells. Next, we expanded the testing of the two most potent GPC2-directed CAR constructs prioritized from these studies to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, locoregional delivery bi-weekly of two to four million GPC2-directed mRNA CAR T cells induced significant and sustained tumor regression in two orthotopic medulloblastoma models, and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells. One Sentence SummaryGlypican 2 is expressed on the surface of multiple pediatric brain tumors and can be successfully targeted with mRNA chimeric antigen receptor T cells.

cancer biology↗