IBB Seminar
"Using Distinct CAR and TCR Signaling Cascades to Enhance Cellular Immunotherapy"
Nicholas R.J. Gascoigne, Ph.D., FRSB
Professor, Immunology Translational Research Programme
Cancer Translational Research Programme
Department of Microbiology and Immunology
Yong Loo Lin School of Medicine
National University of Singapore
*Register HERE to participate via Zoom
CAR-T cells use TCR signaling cassettes coupled to the recognition elements of antibodies. CAR-T technology has achieved significant success in treatment of certain liquid cancers, but many challenges hinder the development of this therapy, for example its efficacy for solid tumours. These challenges show our inadequate understanding of this technology, particularly regarding CAR signaling, and how it may differ from TCR signaling. To dissect CAR signaling, we directly compared a CAR and a TCR targeting the same pMHC antigen, finding that CD28-CAR signaling was triggered in the absence of the SRC family kinase (SFK) LCK, which is essential for TCR signaling. We found that LCK-disrupted CAR-T cells (disLCK-CAR-T) are strongly signaled through CAR and have significantly better in vivo efficacy in both liquid and solid tumor. This is because of their enhanced persistence, induction of memory, and reduced exhaustion phenotype. The disLCK-CAR-T can be further developed as an allogeneic CAR-T. disLCK-CAR-T blocks activation through endogenous TCR equally well as TCR KO CAR-T. It also shows superior in vivo persistence compared to TCR KO T cells, possibly because of retained tonic signaling. This non-canonical signaling in CAR-T cells provides new insight into the initiation of TCR and CAR signaling and has important clinical implications for improvement of both autologous and allogeneic CAR-T cells. Funding: MOE: MOE-000112; NMRC: MOH-000523
Prof. Gascoigne’s research interests are in cellular and molecular immunology, focusing on the regulation of signaling in T cell activation and development. His lab demonstrated the role of TCR binding strength in thymocyte differentiation, and the importance of CDR1,2 TCR sequences in MHC restriction. They utilize Foerster Resonance Energy Transfer (FRET) imaging to analyze interactions between cell surface molecules and demonstrated the importance of coagonism in antigen recognition. His lab identified and characterized Themis, a protein that controls thymocyte positive selection through regulation of TCR signaling strength. He maintains his interests in T cell signaling, activation, development, microbiome-immune system interactions. His lab is currently studying signaling pathways in CAR-T cells and how they can be manipulated to improve CAR-T function in cancer immunotherapy.
This seminar is hosted by Georgia Tech's Institute for Bioengineering and Bioscience (IBB) and Immunoengineering Center.
