A5018305697- CAR-T cell therapy research
- T-cell and B-cell Immunology
- Nanowire Synthesis and Applications
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Nanofabrication and Lithography Techniques
- Monoclonal and Polyclonal Antibodies Research
University of California, San Francisco
2021-2025
Howard Hughes Medical Institute
2021
Designing smarter anticancer T cells Biological signaling systems can exhibit a large, nonlinear—or “ultrasensitive”—response, which would be useful to engineer into therapeutic allow for better discrimination between cancer and normal tissues. Hernandez-Lopez et al. modified human using two-step mechanism that allowed them kill expressing large amounts of marker protein but not small amount the same protein. A first synthetic receptor recognized antigen with low affinity. That signaled...
Chimeric antigen receptor (CAR) costimulatory domains derived from native immune receptors steer the phenotypic output of therapeutic T cells. We constructed a library CARs containing ~2300 synthetic domains, built combinations 13 signaling motifs. These promoted diverse human cell fates, which were sensitive to motif and configurations. Neural networks trained decode combinatorial grammar CAR motifs allowed extraction key design rules. For example, non-native that bind tumor necrosis factor...
To engineer cells that can specifically target the central nervous system (CNS), we identified extracellular CNS-specific antigens, including components of CNS matrix and surface molecules expressed on neurons or glial cells. Synthetic Notch receptors engineered to detect these antigens were used program T induce expression diverse payloads only in brain. CNS-targeted induced chimeric antigen receptor efficiently cleared primary secondary brain tumors without harming cross-reactive outside...
Immune homeostasis requires a balance of inflammatory and suppressive activities. To design cells potentially useful for local immune suppression, we engineered conventional CD4 + T with synthetic Notch (synNotch) receptors driving antigen-triggered production anti-inflammatory payloads. Screening diverse library suppression programs, observed the strongest cytotoxic cell attack by both factors (interleukin-10, transforming growth factor–β1, programmed death ligand 1) sinks proinflammatory...
Abstract Engineered T cell therapies have emerged as a promising approach for cancer treatment, yet their application to solid tumors remains challenging due the limited specificity and persistence of current antigen recognition strategies. Here, we introduced sherpabodies, engineered from human SH3 domain scaffold, class antibody-mimetic proteins capable precise tumor-associated recognition. A phage display library identified sherpabodies against panel popular antigens (TAA), which were...
Abstract Overexpressed tumor associated antigens (e.g. HER2 and EGFR) are attractive targets for therapeutic T cells, but toxic cross-reaction with normal tissues expressing low antigen levels has been observed Chimeric Antigen Receptor (CAR) cells targeting such antigens. Inspired by natural ultrasensitive response circuits, we engineer a two-step positive feedback circuit that allows to discriminate based on sigmoidal density threshold. In this circuit, affinity SynNotch receptor controls...
ABSTRACT Chimeric antigen receptor (CAR) costimulatory domains steer the phenotypic output of therapeutic T cells. In most cases these are derived from native immune receptors, composed signaling motif combinations selected by evolution. To explore if non-natural motifs could drive novel cell fates interest, we constructed a library CARs containing ∼2,300 synthetic domains, built 13 peptide motifs. The produced driving diverse fate outputs, which were sensitive to and configurations. Neural...