A5103074553- CAR-T cell therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- Nanowire Synthesis and Applications
- Glioma Diagnosis and Treatment
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Advancements in Semiconductor Devices and Circuit Design
- Neuroinflammation and Neurodegeneration Mechanisms
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Biosimilars and Bioanalytical Methods
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Monoclonal and Polyclonal Antibodies Research
- Biomedical Ethics and Regulation
- Nanoplatforms for cancer theranostics
- 3D Printing in Biomedical Research
- Cancer Research and Treatments
- Wheat and Barley Genetics and Pathology
- Turfgrass Adaptation and Management
- Silicon Carbide Semiconductor Technologies
- Advanced Electron Microscopy Techniques and Applications
- Chemokine receptors and signaling
- Mesenchymal stem cell research
- Chronic Lymphocytic Leukemia Research
City of Hope
2016-2025
Beckman Research Institute
2016-2024
City Of Hope National Medical Center
2010-2024
CTI BioPharma (United Kingdom)
2016-2023
Agricultural Research & Education Organization
2004
A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated interleukin-13 alpha 2 (IL13Rα2). Multiple infusions of CAR were administered over 220 days through two intracranial delivery routes - into resected tumor cavity followed by ventricular system. Intracranial IL13Rα2-targeted not associated any toxic effects grade 3 or higher. After T-cell treatment, regression all and spinal tumors was observed, along...
Improvements in the quality and fitness of chimeric antigen receptor (CAR)-engineered T cells, through CAR design or manufacturing optimizations, could enhance therapeutic potential CAR-T cells. One parameter influencing effectiveness cell therapy is differentiation status final product: cells that are less-differentiated less exhausted more therapeutically effective. In current study, we demonstrate expanded IL15 (CAR-T/IL15) preserve a stem memory (Tscm) phenotype, defined by expression...
Chimeric antigen receptor–modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding the optimal characteristics cellular products, including appropriate composition CD4+ CD8+ subsets. Here, we investigated differential antitumor effect targeting glioblastoma-associated (GBM-associated) IL-13 receptor α2 (IL13Rα2). Upon stimulation...
CAR T cells using chlorotoxin as the tumor-targeting domain recognize and kill glioblastoma with high specificity potency.
Abstract Chimeric antigen receptor (CAR) T cells mediate potent antigen-specific antitumor activity; however, their indirect effects on the endogenous immune system are not well characterized. Remarkably, we demonstrate that CAR T-cell treatment of mouse syngeneic glioblastoma (GBM) activates intratumoral myeloid and induces memory responses coupled with feed-forward propagation responses. IFNγ production by responsiveness host critical for tumor landscape remodeling to promote a more...
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly current therapies. Here we report completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with the majority being glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose recommended 2 plan. Secondary included overall survival, disease response,...
Glioblastoma (GBM) contains self-renewing GBM stem cells (GSC) potentially amenable to immunologic targeting, but chimeric antigen receptor (CAR) T-cell therapy has demonstrated limited clinical responses in GBM. Here, we interrogated molecular determinants of CAR-mediated killing through whole-genome CRISPR screens both CAR T and patient-derived GSCs. Screening identified dependencies for effector functions, including TLE4 IKZF2. Targeted knockout these genes enhanced antitumor efficacy....
Despite significant infiltration into tumors, the effector function of macrophages (MPs) and microglia (MG) appears to be suppressed in gliomas. Although STAT3 pathway is thought play a role this process, exact mechanism by which gliomas induce activation MPs MG not known. Because receptor for advanced glycation end products (RAGE) can STAT3, because express high levels S100B, RAGE ligand, we hypothesized that MP/MG activity may modulated through S100B-RAGE interaction. Exposure N9 bone...
Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release variety pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro functions dictates antitumor activity. To evaluate potential variations in MG MP function gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS evaluated...
Even when treated with aggressive current therapies, most patients glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits penetration of large molecules into brain, all contribute to poor response associated conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported single-walled carbon nanotubes (SWCNTs) can be used dramatically increase...
Little is known about the penetration and bioactivity of systemically administered programmed cell death 1 (PD-1) antibodies in central nervous system. Such information critical for advancing checkpoint antibody therapies treatment brain tumors.To evaluate pembrolizumab concentrations PD-1 blockade on T cells cerebrospinal fluid (CSF) after intravenous administration.Cerebrospinal blood samples were collected from 10 adult patients with high-grade gliomas who participating clinical trials...
Chimeric antigen receptor (CAR) T cell therapy faces notable limitations in treatment of solid tumors. The suppressive tumor microenvironment (TME), characterized by complex interactions among immune and stromal cells, is gaining recognition conferring resistance to CAR therapy. Despite the abundance diversity macrophages TME, their intricate involvement modulating responses therapies remains poorly understood. Here, we conducted single-cell RNA sequencing (scRNA-seq) on tumors from 41...
Abstract In the evolving landscape of glioblastoma (GBM) treatment, clinical trials exploring chimeric antigen receptor (CAR) T cell therapies have shown promise; however, their therapeutic efficacy remains constrained, particularly due to immunosuppressive tumor microenvironment (TME). Emerging evidence highlights that TME, especially myeloid-driven suppressive networks, plays a central role in resistance CAR therapy. Despite progress elucidating these mechanisms, significant ambiguities...
Abstract Targeting the tumor microenvironment (TME) to be more immune permissive is a potential strategy for enhancing immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, providing promising avenue treating aggressive tumors glioblastoma multiforme (GBM). Tertiary lymphoid structures (TLS) are ectopic aggregates that arise in response chronic inflammation and mimic structure function of secondary organs. The spontaneous presence TLS some solid tumors, including GBM,...
Standard-of-care treatment for Glioblastoma Multiforme (GBM) is comprised of surgery and adjuvant chemoradiation. Chimeric Antigen Receptor (CAR) T cell therapy has demonstrated disease-modifying activity in GBM holds great promise. Radiation, a standard-of-care GBM, well-known immunomodulatory properties may overcome the immunosuppressive tumor microenvironment (TME); however, radiation dose optimization integration with CAR not well defined. Murine immunocompetent models were treated...
Even when treated with aggressive current therapies, patients glioblastoma usually survive less than two years and exhibit a high rate of recurrence. CpG is an oligonucleotide that activates the innate immune system via Toll-like receptor 9 (TLR9) activation. Injection into tumors showed promise as immunotherapy in mouse models but proved disappointing human trials. One aspect glioma not addressed by therapy alone highly invasive nature cells, which associated resistance to radiation...
The field of chimeric antigen receptor (CAR) T cell therapy is rapidly advancing with improvements in CAR design, gene-engineering approaches and manufacturing optimizations. One challenge for these development efforts, however, has been the establishment vitro assays that can robustly inform selection optimal products vivo therapeutic success. Standard tumor-lysis often fail to reflect true antitumor potential cells due relatively short co-culture time high tumor ratio. Here, we describe an...
Chimeric antigen receptor (CAR) T cell immunotherapy is emerging as a powerful strategy for cancer therapy; however, an important safety consideration the potential off-tumor recognition of normal tissue. This particularly ligand-based CARs are optimized clinical translation. Our group has developed and clinically translated IL13(E12Y) CAR targeting IL13Rα2 treatment glioblastoma (GBM). There remains limited understanding how IL13-ligand design impacts activity selectivity intended...
The field of chimeric antigen receptor (CAR) T cell therapy is rapidly advancing with improvements in CAR design, gene-engineering approaches and manufacturing optimizations. One challenge for these development efforts, however, has been the establishment vitro assays that can robustly inform selection optimal products vivo therapeutic success. Standard tumor-lysis often fail to reflect true antitumor potential cells due relatively short co-culture time high tumor ratio. Here, we describe an...
Abstract Chimeric antigen receptor (CAR) T-cell therapy has transformed clinical care against blood malignancies and is seeing encouraging progress solid tumors. While scientific advancement been rapid, our mechanistic understanding of intrinsic features CAR-engineered T cells still evolving. CAR products typically consist CD4+ CD8+ subsets at variable ratios, yet a clear how each subset contributes together independently to therapeutic response lacking. are well characterized for their...
T cell immunotherapy is emerging as a powerful strategy to treat cancer, and may offer opportunities improve outcomes for patients with glioblastoma (GBM). We have optimized chimeric antigen receptor (CAR) therapy targeting the GBM-associated IL13Rα2 that utilizes CD62L-enriched central memory cells (Tcm) engineered by lentiviral transduction express second-generation 4-1BB-containing CAR (IL13BBζ). report here initial findings from our first-in-human clinical trial [NCT02208362]. The aims...
T cell immunotherapy is emerging as a powerful strategy to treat cancer, and may offer new opportunities improve outcomes for patients with glioblastoma (GBM), the most aggressive of primary brain tumors among lethal human cancers. We have optimized chimeric antigen receptor (CAR) therapy targeting tumor associated IL13Rα2 treatment GBM. This product utilizes CD62L-enriched central memory cells (Tcm), engineered by lentiviral transduction express second-generation 4-1BB-containing CAR...