A5035289183- CAR-T cell therapy research
- Immune Cell Function and Interaction
- CRISPR and Genetic Engineering
- Immunotherapy and Immune Responses
- Adenosine and Purinergic Signaling
- Phagocytosis and Immune Regulation
- Cytomegalovirus and herpesvirus research
- T-cell and B-cell Immunology
- Virus-based gene therapy research
- Single-cell and spatial transcriptomics
Stanford University
2021-2024
Stratford University
2022
Stanford Cancer Institute
2022
T cells are the major arm of immune system responsible for controlling and regressing cancers. To identify genes limiting cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) cells. Top hits were
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 CD73, which mediate proximal steps Ado generation. Here, we sought to enhance cell potency by knocking out CD39, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of deaminase (ADA-OE), metabolizes inosine (INO), induced stemness enhanced functionality. Similarly, exposure INO augmented function features stemness. profound metabolic...
Abstract Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of immune system 1,2 . Here we administered anti-CD47 antibodies in combination with adoptively goal enhancing antitumour efficacy but observed abrogated therapeutic benefit due rapid macrophage-mediated clearance expressing chimeric antigen receptors (CARs) or engineered cell receptors. Anti-CD47-antibody-mediated CAR was potent enough serve...
Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR engineered from a novel humanized CD93-specific binder potently kill AML in vitro and vivo spare hematopoietic stem progenitor (HSPC). No toxicity is seen murine models, expressed on human endothelial cells, recognize cell lines. identify other T-cell with overlapping expression especially context proinflammatory...
Abstract T cell exhaustion limits anti-tumor immunity, but the molecular determinants of this process remain poorly understood. Using a chronic antigen stimulation assay, we performed genome-wide CRISPR/Cas9 screens to systematically discover genetic regulators exhaustion, which identified an enrichment epigenetic factors. In vivo CRISPR in murine and human tumor models demonstrated that perturbation several regulators, including members INO80 BAF chromatin remodeling complexes, improved...
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8
Abstract Adoptively transferred T cells and agents designed to block the CD47/SIRPα axis are promising antitumor therapeutics, which activate distinct arms of immune system. We administered anti-CD47 (αCD47) with adoptively goal enhancing efficacy but observed rapid macrophage-mediated clearance expressing chimeric antigen receptors (CARs) or engineered cell receptors, blunted therapeutic benefit. αCD47 mediated CAR was potent enough serve as an effective safety switch. To overcome this...
Abstract Chimeric antigen receptor T (CAR T) cells are synthetically engineered to target specific tumor antigens. CD47 is a ubiquitous that serves as “don’t eat me” signal by binding SIRPɑ on macrophages and often over-expressed cancer cells. Despite individual promise of CAR anti-CD47 therapies, neither has demonstrated clear efficacy in treating solid tumors the clinic there thus an urgent need develop novel approaches enhance potency these therapies. We interrogated potential pairing...
<div>Abstract<p>Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR engineered from a novel humanized CD93-specific binder potently kill AML <i>in vitro</i> and vivo</i> spare hematopoietic stem progenitor (HSPC). No toxicity is seen in murine models, expressed on human endothelial cells, recognize cell lines. identify other T-cell with...
<div>Abstract<p>Chimeric antigen receptor (CAR) T cells hold promise for the treatment of acute myeloid leukemia (AML), but optimal targets remain to be defined. We demonstrate that CD93 CAR engineered from a novel humanized CD93-specific binder potently kill AML <i>in vitro</i> and vivo</i> spare hematopoietic stem progenitor (HSPC). No toxicity is seen in murine models, expressed on human endothelial cells, recognize cell lines. identify other T-cell with...
<p>Supplemental figures and legends in one document</p>
<p>Supplemental figures and legends in one document</p>
<h3>Background</h3> In acute myelogenous leukemia (AML), CD93 is an appealing target for chimeric antigen receptor (CAR) T-cell therapy, offering leukemic killing without myelosuppression in preclinical studies.<sup>1</sup> However, CAR development hampered by expression on healthy endothelium. Our group previously demonstrated the efficacy of inhibitory (iCAR) to counteract off-tumor CD93-directed activating (aCAR) signaling a model system.<sup>1</sup> Here, we identify endothelial-specific...
<h3>Background</h3> CAR T cells have been highly effective against refractory B cell malignancies but not demonstrated sustained antitumor effects solid tumors. Intense effort is underway to augment the potency of in order overcome suppressive tumor microenvironment, which associated with exhaustion. Adenosine a major mediator immune suppression. CD39 (ecto-ATP diphosphohydrolase-1) plays central role generation adenosine by catalyzing metabolism ATP into ADP/AMP. CD73 (59-ectonucleotidase)...
Abstract Adoptive T cell immune therapies mediate impressive clinical benefit in a fraction of patients, but anti-tumor effects are often limited by inadequate potency. To identify genes that limit effector function, we conducted genome-wide CRISPR knock-out screens human primary CAR-T cells. The top hits were components the CDK8 kinase module Mediator complex, an evolutionarily conserved regulator gene transcription. deficient cells manifest increased expansion, cytokine production,...
Abstract Chimeric Antigen Receptor (CAR) T cell therapy has resulted in remarkable clinical outcomes the context of acute and chronic lymphoblastic leukemia, but remains unsuccessful treatment solid tumors. One reason for this failure is thought to be dysfunction or exhaustion promoted by suppressive soluble factors within tumor microenvironment (TME). High extracellular levels immunosuppressive factor adenosine (Ado) are generated TME via breakdown ATP ecto-enzymes CD39 CD73 expressed on...
Abstract Adoptive T cell immune therapies mediate impressive clinical benefit in a fraction of patients, but anti-tumor effects are often limited by inadequate potency. To identify genes limiting effector function, we conducted genome-wide CRISPR knock-out screens human primary CAR-T cells. The top hits were MED12 and CCNC , components the cyclin-dependent kinase (CDK) module Mediator complex, an evolutionarily conserved regulator gene transcription. or deficient cells manifest increased...