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SUMMARY:CCSB Seminar Series: Kyle Daniels\, PhD\, March 21
DESCRIPTION:Stanford Center for Cancer Systems Biology \n– Seminar Series – 2025 \nKyle Daniels\, PhD \nAssistant Professor of Genetics and\, by courtesy\, of Neurosurgery\, Stanford University \nMapping the structure-signaling-phenotype landscape in CAR T cells using synthetic signaling protein arrays and machine learning \n  \nChimeric antigen receptor (CAR) T cells are powerful therapeutics for cancers. These CAR T cell therapies can be improved by providing JAK/STAT signaling to increase CAR T cell survival\, proliferation\, and anti-tumor activity. To design proteins that enhance CAR T cell efficacy\, we sought to map the structure of JAK/STAT signaling domains to cell signaling and resulting CAR T cell phenotype. We recombined 14 signaling motifs to construct library of ~30\,000 constitutively active synthetic cytokine receptors (SCRs) with intracellular domains composed of novel signaling motif combinations that activate different signaling cascades. We experimentally tested ~530 SCRs which generated a range of CAR T cell memory\, cytotoxicity\, and proliferation. To map the structure-signaling-phenotype landscape we trained models to predict CAR T cell signaling and phenotype that result from various motif combinations. Modeling also revealed a trade-off between memory and cytotoxicity\, with a Pareto front defined by cell signaling. We identified signaling features associated with memory\, cytotoxicity\, or a balance between the two. SCRs with balanced pSTAT1/3/5 signaling encoded balanced memory and cytotoxicity to enhance CAR T cell tumor control in a mouse model of osteosarcoma. We also identified signaling features that promote unsafe autonomous CAR T cell proliferation. These findings demonstrate that combinatorial screening and machine learning can be combined to map the structure-signaling-function landscape of synthetic proteins in therapeutic immune cells. This approach and the resulting models may enable rational design of CAR T cells with improved cytotoxicity\, memory\, and safety profiles. \nFriday\, March 21\, 2025 \nClark Center\, S360\, 3rd floor \n11:00AM -12:00PM \nRefreshments will be provided
URL:https://dbds.stanford.edu/event/ccsb-seminar-series-kyle-daniels-phd-march-21/
LOCATION:Clark Center S360
ATTACH;FMTTYPE=image/jpeg:https://dbds.stanford.edu/wp-content/uploads/2025/01/kyle.jpg
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