A5058544113- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- CRISPR and Genetic Engineering
- Nanowire Synthesis and Applications
- Gene Regulatory Network Analysis
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Nanofabrication and Lithography Techniques
- Viral Infectious Diseases and Gene Expression in Insects
- RNA and protein synthesis mechanisms
- Virus-based gene therapy research
- Galectins and Cancer Biology
- Advancements in Semiconductor Devices and Circuit Design
- Cancer Immunotherapy and Biomarkers
- Biosimilars and Bioanalytical Methods
- Genetic Associations and Epidemiology
- Cancer Research and Treatments
- Inflammatory Biomarkers in Disease Prognosis
- dental development and anomalies
- Photoreceptor and optogenetics research
- Pluripotent Stem Cells Research
- Nutrition, Genetics, and Disease
- Genomics and Chromatin Dynamics
- Receptor Mechanisms and Signaling
University of Pittsburgh
2016-2025
Institute of Immunology
2025
UPMC Hillman Cancer Center
2019-2024
Tsinghua University
2021
Harvard University
2006-2014
Center for Systems Biology
2010-2014
Broad Institute
2006-2013
Brown University
2006-2007
John Brown University
2007
Massachusetts General Hospital
2006
Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) are engineered cell-surface that sense a target respond by activating T cell receptor signaling or customized gene program, respectively. Here, to expand the targeting capabilities of these receptors, we develop "universal" systems for which specificity can be directed post-translationally via covalent attachment co-administered antibody bearing benzylguanine (BG) motif. A SNAPtag self-labeling enzyme is genetically fused...
The ability to engineer biological circuits that process and respond complex cellular signals has the potential impact many areas of biology medicine. Transcriptional activator-like effectors (TALEs) have emerged as an attractive component for engineering these circuits, TALEs can be designed de novo target a given DNA sequence. Currently, however, use is limited by degeneracy in site-specific manner which they recognize DNA. Here, we propose algorithm computationally address this problem....
Chimeric antigen receptor T cells (CAR-Ts) are promising cancer therapeutics. However, since can lose the CAR-targeted and avoid destruction, targeting multiple antigens with CARs has been proposed. We illustrate here a less cumbersome alternative, anti-tag (AT-CARs) that bind to tags on tumor-targeting antibodies. have created novel AT-CARs, using affinity-enhanced monomeric streptavidin 2 (mSA2) biotin-binding domain when expressed target coated biotinylated Human expressing mSA2 CD28-CD3ζ...
The ability to perform molecular-level computation in mammalian cells has the potential enable a new wave of sophisticated cell-based therapies and diagnostics. To this end, we developed Boolean logic framework utilizing artificial Cys(2)-His(2) zinc finger transcription factors (ZF-TFs) as computing elements. Artificial ZFs can be designed specifically bind different DNA sequences thus comprise diverse set components ideal for construction scalable networks. We generate ZF-TF activators...
Cellular immunotherapies for cancer represent a means by which patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral cells tumor targets, showing remarkable potency in blood cancers. However, due several resistance mechanisms, CAR-T cell therapies remain ineffective solid tumors. We and others have shown the microenvironment harbors distinct metabolic landscape that...
The transmembrane receptor Tim-3 is recruited to the immune synapse of T cells, where it provides costimulatory signals.
Abstract MUC1 is a shared tumor antigen expressed on >80% of human cancers. We completed the first prophylactic cancer vaccine clinical trial based non-viral antigen, MUC1, in healthy individuals at-risk for colon cancer. This provided unique source potentially effective and safe immunotherapeutic drugs, fully-human antibodies affinity-matured host to antigen. purified, cloned, characterized 13 IgGs specific several tumor-associated epitopes with wide range binding affinities. These bind...
As living drugs, engineered T cell therapies are revolutionizing disease treatment with their unique functional capabilities. However, they suffer from limitations of potentially unpredictable behavior, toxicities, and nontraditional pharmacokinetics. Engineering conditional control mechanisms responsive to tractable stimuli such as small molecules or light is thus highly desirable. We others previously developed "universal" chimeric antigen receptors (CARs) that interact coadministered...
SNAP-tag, a mutant of the O6-alkylguanine-DNA-alkyltransferase, self-labels by reacting with benzylguanine (BG) substrates, thereby forming thioether bond. SNAP-tag has been genetically fused to wide range proteins interest in order covalently modify them. In context both diagnostic and therapeutic applications, as well use biological recording device, precise control spatial temporal fashion over covalent bond-forming reaction is desired direct inputs, readouts, or actions specific...
The lack of CAR-T cell infiltration and immune-mediated cancer destruction is a dominant mechanism immunotherapy failure. characteristics mechanisms cognate recognition induced have yet to be revealed. In this study, we developed an in-vitro 3D collagen droplet co-culture system simulate in the tumor microenvironment track T motility interactions with cells real-time under different micro physiological environments. We employed overexpressing SNAP tag (SNAP-CAR cells), where contacts between...
Conditional protein splicing is a powerful biotechnological tool that can be used to rapidly and post-translationally control the activity of given protein. Here we demonstrate novel conditional system in which genetically encoded scaffold induces activation an enzyme mammalian cells. In this binds two inactive split intein/enzyme extein fragments leading intein fragment complementation, splicing, firefly luciferase enzyme. We first ability antiparallel coiled-coils (CCs) mediate between...
The abnormal hypoglycosylated form of the epithelial mucin MUC1 is over-expressed in chronic inflammation and on human adenocarcinomas, suggesting its potential role inflammation-driven tumorigenesis. presence aggravates colonic increases tumor initiation progression an vivo AOM/DSS mouse model colitis-associated cancer (CAC). High expression levels pro-inflammatory cytokines, including TNF-α IL-6, were found MUC1+ inflamed colon tissues. Exogenous promoted transcriptional activity as well...
The success of chimeric antigen receptor (CAR) T cells in blood cancers has intensified efforts to develop CAR therapies for solid cancers. In the tumor microenvironment, cell trafficking and suppression cytotoxic killing represent limiting factors therapeutic efficacy. Here, we present a microwell platform study interactions with 3D breast spheroids determine predictors anti-tumor function. To precisely control sensing, utilized switchable adaptor system that covalently attaches...
As living drugs, engineered T cell therapies are revolutionizing disease treatment with their unique functional capabilities. However, they suffer from limitations of potentially unpredictable behavior, toxicities, and non-traditional pharmacokinetics. Engineering conditional control mechanisms responsive to tractable stimuli such as small molecules or light is thus highly desirable. We others previously developed "universal" chimeric antigen receptors (CARs) that interact co-administered...
Abstract Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) are engineered cell-surface that sense a target respond by activating T cell receptor signaling or customized gene program, respectively. To expand the targeting capabilities of these receptors, we have developed switchable adaptor systems for which specificity can be directed post-translationally via covalent attachment co-administered antibody. Instead directly an antigen, our contain SNAPtag self-labeling enzyme,...
The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T biology an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), component the TGFβ expressed surface certain solid tumors and acute leukemias. CD105-targeted cells can be grown from various backgrounds, tracked vivo by congenic marks, activated isolation or tumor cells. were toxic at higher...
In 2000, Gardner and Collins reported the construction of a fundamental genetic regulatory device, bi-stable toggle switch, in E. coli. We report here our work on natural extension this powerful tri-stable switch capable switching among three stable states. Like consists repressible promoters that produce inhibitory proteins requires only transient pulse chemical inducer to Our proof-of-principal construct is designed control expression different fluorescent reporters using pBad/AraC,...
<h3>Background</h3> Chimeric antigen receptors (CAR) have demonstrated remarkable efficacy in licensing T cells for antitumor responses against hematopoietic malignancies but had limited success solid tumors. Macrophages, both archetypic phagocytes and professional presenting cells, may exert profound effector functions which complement adaptive cellular immunity.<sup>1</sup> Recently, it was shown that human macrophages engineered to express CARs (CAR-Ms) antigen-specific phagocytosis,...