A5069287999- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Viral Infectious Diseases and Gene Expression in Insects
- Silicon Carbide Semiconductor Technologies
- T-cell and B-cell Immunology
- CRISPR and Genetic Engineering
- Immunotherapy and Immune Responses
- Nanowire Synthesis and Applications
- Virus-based gene therapy research
- Cancer Immunotherapy and Biomarkers
- Advancements in Semiconductor Devices and Circuit Design
- Immune cells in cancer
- Ubiquitin and proteasome pathways
- RNA Interference and Gene Delivery
- RNA regulation and disease
- Immunodeficiency and Autoimmune Disorders
- interferon and immune responses
- Escherichia coli research studies
- Synthesis and Biological Evaluation
- Integrated Circuits and Semiconductor Failure Analysis
- Hematopoietic Stem Cell Transplantation
- Endoplasmic Reticulum Stress and Disease
- Biosimilars and Bioanalytical Methods
- Reproductive System and Pregnancy
- Chronic Lymphocytic Leukemia Research
Moffitt Cancer Center
2017-2025
University of Miami
2013-2021
University of South Florida
2020
Clinical Science Institute
2019
Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both achieve similar clinical outcomes, biologic differences become apparent but not completely understood. Therefore, in this study we aimed identify mechanistic between costimulation that contribute the 2 could be exploited enhance CAR T cell function. Using CD19-targeted cells...
Background Co-stimulatory signals regulate the expansion, persistence, and function of chimeric antigen receptor (CAR) T cells. Most studies have focused on co-stimulatory domains CD28 or 4-1BB. CAR cell persistence is enhanced by 4-1BB co-stimulation leading to nuclear factor kappa B (NF-κB) signaling, while resistance exhaustion mutations domain. Methods We hypothesized that a third-generation containing with only PYAP signaling motif (mut06) would provide beneficial aspects both. designed...
An obstacle to the development of chimeric antigen receptor (CAR) T cells is limited understanding CAR T-cell biology and mechanisms behind their antitumor activity. We others have shown that CARs with a CD28 costimulatory domain drive high activation, which leads exhaustion shortened persistence. This work led us hypothesize by incorporating null mutations subdomains (YMNM, PRRP, or PYAP), we could optimize costimulation enhance function.
Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy impairment graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T for prevention. CD83 expressed on allo-activated...
Abstract Background KRAS mutations frequently occur in cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. Although G12C inhibitors have recently been approved, effective precision therapies not yet established for all -mutant cancers. Many treatments including epigenome-targeted drugs, are currently under investigation. Small ubiquitin-like modifier (SUMO) proteins a family of small covalently attached to detached from other cells via...
Background In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As cell-based therapies often fail to work in solid tumors, this study aims investigate effects of on cell topo-distribution TME, gene expression association with states, and clinical responses melanoma. Methods To generate detailed information oxygenation accessibility, we used mathematical modeling human melanoma tissue microarrays...
CAR-T therapy has led to significant improvements in patient survival. However, a subset of patients experience high-grade toxicities, including cytokine release syndrome (CRS) and immune cell-associated hematologic toxicity (ICAHT). We utilized IL-2Rα knockout mice model toxicities with elevated levels IL6, IFNγ, TNFα increased M1-like macrophages. Onset CRS was accompanied by reduction peripheral blood neutrophils due disruption bone marrow neutrophil homeostasis characterized an increase...
<title>Abstract</title> Chimeric antigen receptor (CAR) T cell therapies have revolutionized B malignancy treatment, but subsets of patients with large lymphoma (LBCL) experience primary resistance or relapse after CAR treatment. To uncover tumor microenvironment (TME)-induced mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels immunoregulatory macrophages in pre-infusion biopsies are correlated poor clinical responses. cell-produced...
CD33 and CD123 are expressed on the surface of human acute myeloid leukemia blasts other noncancerous tissues such as hematopoietic stem cells. On-target off-tumor toxicities may limit chimeric antigen receptor T cell therapies that target both CD123. To overcome this limitation, we developed bispecific CD33/CD123 (CAR) cells with an "AND" logic gate. We produced novel scFvs from monoclonal antibodies bound activated Screening CAR for cytotoxicity, cytokine production, proliferation was...
ABSTRACT Broadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential protection against multiple clades. However, vaccines capable of stimulating production bNAbs remain a major challenge. Given that polyreactivity and autoreactivity considered important characteristics anti-HIV bNAbs, we designed an HIV vaccine incorporating molecular adjuvants BAFF (B cell activating factor) APRIL (a proliferation-inducing ligand) with...
ABSTRACT The host-encoded Perforin-2 (encoded by the macrophage-expressed gene 1, Mpeg1 ), which possesses a pore-forming MACPF domain, reduces viability of bacterial pathogens that reside within membrane-bound compartments. Here, it is shown also restricts proliferation intracytosolic pathogen Listeria monocytogenes . Within few hours systemic infection, massive L. in Perforin -2 −/− mice leads to rapid appearance acute disease symptoms. We go on show cultured cells vacuole-to-cytosol...
Higher γδ T cell counts in patients with malignancies are associated better survival. However, cells rare the blood and functionally impaired malignancies. Promising results reported on treatment of various vivo expansion autologous using zoledronic acid (zol) interleukin-2 (IL-2). Here we demonstrated that zol IL-2, combination a novel genetically engineered K-562 CD3scFv/CD137L/CD28scFv/IL15RA quadruplet artificial antigen-presenting (aAPC), efficiently expand allogeneic donor-derived Good...
Adoptive cell therapy with ex vivo expanded tumor infiltrating lymphocytes or gene engineering T cells expressing chimeric antigen receptors (CAR) is a promising treatment for cancer patients. This production utilizes T-cell activation and transduction beads RetroNectin, respectively. However, the high cost of an obstacle broad clinical application novel immunotherapeutic products. To facilitate we refined our approach by using artificial presenting (aAPCs) that ligate CD3, CD28, CD137...
The host employs both cell-autonomous and system-level responses to limit pathogen replication in the initial stages of infection. Previously, we reported that eukaryotic initiation factor 2α (eIF2α) kinases heme-regulated inhibitor (HRI) protein kinase R (PKR) control distinct cellular immune-related activities response diverse bacterial pathogens. Specifically for Listeria monocytogenes, there was reduced translocation cytosolic compartment HRI-deficient cells consequently loading...
Here we show that cells lacking the heme-regulated inhibitor (HRI) are highly resistant to infection by bacterial pathogens. By examining process in wild-type and HRI null cells, found is required for pathogens execute their virulence-associated cellular activities. Specifically, unlike infected with gram-negative pathogen Yersinia essentially impervious cytoskeleton-damaging effects of Yop virulence factors. This effect due reduced functioning type 3 secretion (T3S) system which injects...
While apoptosis plays a role in B-cell self-tolerance, its significance preventing autoimmunity remains unclear. Here, we report that dysregulated B cell leads to delayed onset autoimmune phenotype mice. Our longitudinal studies revealed mice with cell-specific deletion of pro-apoptotic Bim (BBimfl/fl ) have an expanded compartment notable increase transitional, antibody secreting and recently described double negative (DN) cells. They develop greater hypergammaglobulinemia than lacking all...
Abstract The therapeutic promise of chimeric antigen receptor (CAR) T cells was realized when complete remission rates 90% were reported after treating B cell acute lymphoblastic leukemia (B-ALL) with CD19-targeted CAR cells. However, increasing numbers patients treated, challenges have become evident, especially regarding poor responses, which might be caused by exhaustion. Detailed understanding the mechanism CD28-dependent exhaustion in will allow design a less prone to and reduce relapse...
Abstract The role of natural killer group 2D (NKG2D) in peripheral T cells as a costimulatory receptor is well established. However, its contribution to cell thymic education and functional imprint unknown. Here, we report significant changes development, signaling, transcriptional program, function from mice lacking NKG2D signaling. In C57BL/6 (B6) OT-I mice, found that deficiency results Vβ chain usage stagnation the double-positive stage development. We expression CD5 CD45 thymocytes...