A5068873093- CAR-T cell therapy research
- Advancements in Semiconductor Devices and Circuit Design
- Calcium signaling and nucleotide metabolism
- Immunotherapy and Immune Responses
- Nanowire Synthesis and Applications
- Monoclonal and Polyclonal Antibodies Research
- Adenosine and Purinergic Signaling
- T-cell and B-cell Immunology
- Glioma Diagnosis and Treatment
- Biosimilars and Bioanalytical Methods
- Viral Infectious Diseases and Gene Expression in Insects
- Cytomegalovirus and herpesvirus research
- Immune Cell Function and Interaction
- Autophagy in Disease and Therapy
Oregon Health & Science University
2024-2025
Lyell Immunopharma (United States)
2022-2024
University of California, San Francisco
2020-2021
Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack ideal target antigens that are both absolutely tumor specific and homogeneously expressed. We show multi-antigen prime-and-kill recognition circuits provide flexibility precision to overcome these challenges in context glioblastoma. A synNotch recognizes a priming antigen, such as heterogeneous but tumor-specific glioblastoma neoantigen epidermal growth factor splice variant III (EGFRvIII) or...
Abstract Despite the potential for tumor-specific T cells to mediate durable complete responses of advanced disease, no CAR-T cell treatment is currently approved use against a solid cancer. While nearly all cancers express tumor-associated antigen (TAA) vulnerable CAR recognition, same TAAs are also present on healthy tissues. recognize and attack tissues that their target, even at low levels, provoking lethal dose-limiting ‘on-target off-tumor’ toxicities, most commonly lungs, resulting in...
Abstract Effective antitumor T cell response necessitates nutrient uptake and utilization. Here, we demonstrate that potassium (K+) accumulation within the tumor microenvironment (TME) drives adaptive changes in metabolism via K+-dependent lysosomal acidification. We found acidification promotes a catabolic state CD8+ cells persists independently of extracellular glucose levels (i.e. functional caloric restriction) limits effector functions while enhancing persistence.We previously...
ABSTRACT Treatment of solid cancers with chimeric antigen receptor (CAR) T cells is plagued by the lack target antigens that are both tumor-specific and homogeneously expressed. We show multiantigen prime-and-kill recognition circuits have flexibility precision to overcome these challenges in attacking glioblastoma. A synNotch recognizes a specific priming – heterogeneous glioblastoma neoantigen EGFRvIII or brain tissue-specific used locally induce expression CAR, enabling thorough but...
<h3>Background</h3> Effective solid tumor cell therapy requires new strategies to improve T-cell activation, persistence, and durable function.<sup><sup>1 2</sup></sup> We developed four complementary, stackable reprogramming technologies enhance chimeric antigen receptor (CAR) in tumors: 1) overexpression of the activator protein 1 (AP-1) family transcription factor c-Jun delay exhaustion functional activity<sup><sup>1 3 4</sup></sup>; 2) nuclear subfamily 4A member (NR4A3) gene knock-out...
Abstract Effective solid tumor cell therapy requires new strategies to improve T-cell activation, persistence, and durable function. We developed four complementary reprogramming technologies enhance chimeric antigen receptor (CAR) in tumors: 1) overexpression of the activator protein 1 (AP-1) family transcription factor c-Jun delay exhaustion antitumor activity; 2) nuclear subfamily 4A member 3 (NR4A3) gene knockout (KO) further functionality; 3) Epi-RTM manufacturing protocols preserve...
Abstract We discovered that high extracellular potassium (↑[K+]e) within tumors limits T cell effector function and exhaustion. Moreover, the existing model of K+ transport in cells could not account for our results. Specifically, ↑[K+]e constrained activation exhaustion independent its impact upon membrane potential (Vm) or Ca2+ influx. Rather, controlled state by elevating intracellular ([K+]i), limiting Akt-mTOR signaling inducing a autophagy despite exogenous nutrient sufficiency (Eil...
<h3>Background</h3> Despite the potential for tumor-specific T cells to mediate durable complete responses, even in advanced disease, no CAR-T cell treatment is currently approved use against any solid cancers.<sup>1–3</sup> While a large majority of cancers express tumor-associated antigens (TAAs) that are vulnerable CAR recognition, nearly all cases TAAs present healthy tissues.<sup>4</sup> Since cannot differentiate between cancer and normal cells, recognition on tissues provokes...
Abstract Treatment of solid cancers with chimeric antigen receptor (CAR) T-cells is challenging because a lack target antigens that are both tumor-specific and homogenously expressed. While epidermal growth factor (EGFR)vIII represents glioblastoma (GBM)-specific antigen, its expression heterogeneous within the tumor resulting in escape. In contrast, more expressed GBM-associated (GAA), such as EphA2, non-ideal other normal organs, yielding potential cross-reactive toxicity. As way to safely...
<h3>Background</h3> CART-cell therapy has shown clinical success in treating hematologic cancers. However, more effective CAR T-cell therapies are needed for the treatment of solid tumors. activation is a formative event that directs cell fate and function mature T cells. In context cellular product derivation, these decisions critically impact phenotypic functional quality drug product. We hypothesized optimization signaling parameters during can generate potent <h3>Methods</h3> To control...