A5038828377- CAR-T cell therapy research
- Single-cell and spatial transcriptomics
- Immune cells in cancer
- Viral Infectious Diseases and Gene Expression in Insects
- 3D Printing in Biomedical Research
- Phagocytosis and Immune Regulation
- Immunotherapy and Immune Responses
- Extracellular vesicles in disease
- Cell Image Analysis Techniques
- T-cell and B-cell Immunology
- Mathematical Biology Tumor Growth
- Nanowire Synthesis and Applications
- Biosimilars and Bioanalytical Methods
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Optical Coatings and Gratings
St. Jude Children's Research Hospital
2022-2024
University of Tennessee Health Science Center
2023-2024
Abstract Understanding the intricate dynamics between adoptively transferred immune cells and brain tumor microenvironment (TIME) is crucial for development of effective T cell–based immunotherapies. In this study, we investigated influence TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, evaluated a panel seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory, activation domains. We...
Abstract Outcomes for pediatric patients with diffuse midline glioma (DMG) and relapsed/refractory CNS malignancies remain poor. Loc3CAR is an ongoing, first-in-human, phase I clinical trial (NCT05835687) evaluating intracranial delivery of B7-H3-CAR T cells expressing 41BB ligand (B7-H3-CAR-T) ≤21 years old i) B7-H3+ tumors (Cohort A), or ii) DMG post-radiation B). Treatment included 6 intracerebroventricular B7-H3-CAR-T infusions administered over 7 weeks. Primary secondary outcomes were...
<h3>Background</h3> Chimeric antigen receptor (CAR) T cell therapies have been successfully used to treat several hematological malignancies, resulting in six FDA approvals. However, both clinical and preclinical settings, significant variation efficacy exists when CAR cells are generated from different patient or healthy donor cells. It is unclear what causes this variability either setting, but one source of includes differences function biology between patients donors. The goal study...
Abstract Understanding interactions between adoptively transferred immune cells and the tumor microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated impact of TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3-specific CAR T-cells. We show that five out six B7-H3 CARs with varying transmembrane, co-stimulatory, activation domains, exhibit robust functionality in vitro . However, an immunocompetent glioma model,...
Abstract Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors and a leading cause of cancer-related death in children. There is currently no cure for DIPG, highlighting an urgent need novel therapeutics. Chimeric antigen receptor (CAR)-engineered T-cell therapy offers great promise DIPG treatment; however, several limitations to be addressed. In this study, we targeted tumor associated GRP78 after showing it reliably expressed on the cell surface DIPGs. To test...
Abstract BACKGROUND Diffuse intrinsic pontine gliomas (DIPGs) are highly lethal pediatric brain tumors and a leading cause of cancer-related death in children. There is currently no cure for DIPG, highlighting an urgent need novel therapeutics. Chimeric antigen receptor (CAR)-T-cell therapy offers great promise DIPG treatment; however, several limitations to be addressed. The goal this study identify why CAR T cells ineffective against overcome roadblock by improving the immune synapse (IS),...
Abstract BACKGROUND The infiltrative growth patterns and restrictiveness of the blood brain barrier greatly limit therapeutic options for children diagnosed with diffuse intrinsic pontine gliomas (DIPGs). However, clinical trials using chimeric antigen receptor (CAR)-T cells have shown promise in DIPG patients. Despite some success, biological limitations plaguing CAR-T hinder their overall efficacy. We propose that leveraging chemical compounds tandem may provide an increased benefit...
<h3>Background</h3> Chimeric antigen receptor (CAR) T cell therapies have been used to effectively treat several hematological malignancies, resulting in six FDA approvals. However, even within these approved therapies, significant variation response exists between patients. Interestingly, similar CAR efficacy is also observed the laboratory setting cells generated from different healthy peripheral blood mononuclear (PBMC) donors. Although it unclear what causes either setting, one...
<div>Abstract<p>Understanding the intricate dynamics between adoptively transferred immune cells and brain tumor microenvironment (TIME) is crucial for development of effective T cell–based immunotherapies. In this study, we investigated influence TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, evaluated a panel seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory,...
<p>Supplementary Figure S11 shows dot plots depicting differentially expressed T cell genes in clusters per treatment group.</p>
<p>Supplementary Figure S7 shows initial analysis of scRNAseq data.</p>
<p>Supplementary Figure S9 shows cluster frequency per treatment group for each cluster.</p>
<p>Supplementary Figure S9 shows cluster frequency per treatment group for each cluster.</p>
<p>Generation and functional characterization of syngeneic B7-H3 CAR T-cells with different structural designs. <b>A,</b> Scheme mB7-H3-CAR constructs. Created BioRender.com. <b>B,</b> MTS cytotoxicity assay against GL261 tumor cells at an E:T ratio 0.25:1 (<i>n</i> = 7, mean ± SD, two-way ANOVA Tukey test for multiple comparisons). <b>C,</b> T expressing mB7-H3 constructs were cocultured a 2:1 restimulation every 3 days fresh until they...
<div>Abstract<p>Understanding the intricate dynamics between adoptively transferred immune cells and brain tumor microenvironment (TIME) is crucial for development of effective T cell–based immunotherapies. In this study, we investigated influence TIME chimeric antigen receptor (CAR) design on anti-glioma activity B7-H3–specific CAR T-cells. Using an immunocompetent glioma model, evaluated a panel seven fully murine B7-H3 CARs with variations in transmembrane, costimulatory,...
<p>Supplementary Figure S15 shows GSEA of hallmark pathways in macrophage subclusters.</p>
<p>Global Mac/MG depletion abrogates effective CAR T-cell responses. GL261 glioma-bearing mice were treated with BLZ945 at 200 mg/kg starting 5 days after tumor implantation. <b>A,</b> Experimental scheme of macrophage kinetics experiment. Daily drug dosing via oral gavage was for 2 weeks and tumors harvested FACS analysis 9, 16, 20 <b>B,</b> Summary plot showing frequency TAMs infiltrating as percentage live CD45<sup>+</sup> immune cells....
<p>Supplementary Figure S7 shows initial analysis of scRNAseq data.</p>
<p>Supplementary Figure S5 shows murine CAR T cell expansion in media and after exposure to B7-H3-negative tumor cells.</p>
<p>CAR structural design significantly impacts anti-glioma efficacy of mB7-H3 CAR T-cells in the GL261 immunocompetent model. Albino C57BL/6 mice were transplanted with 1 × 10<sup>5</sup> cells orthotopically, followed 7 days later by intratumoral injection 3 10<sup>6</sup> mB7-H3-CAR transduced different constructs and adjusted to 40% expression. <b>A,</b> Axial brain MRI images from representative per treatment group at 16 29 after tumor...
<p>Supplementary Figure S3 shows expression of murine B7-H3 CARs in producer cells and T cells.</p>
<p>Supplementary Figure S1 shows murine CAR T cell efficacy in vivo and Cd276 IHC post-treatment.</p>
<p>Supplementary Figure S17 shows testing of BLZ945 effect on CAR T cell in vitro.</p>