Journal Article Ppublish 1 citation
PubMed: 40220754 DOI: 10.1016/j.cell.2025.03.017
Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.
Cell 188(9):2372-2389.e35
Authors: Taisuke Kondo, François X P Bourassa, Sooraj Achar, Justyn DuSold, Pablo F Céspedes, Makoto Ando, Alka Dwivedi, Josquin Moraly, Christopher Chien, Saliha Majdoul, Adam L Kenet, Madison Wahlsten, Audun Kvalvaag, Edward Jenkins, Sanghyun P Kim, Catherine M Ade, Zhiya Yu, Guillaume Gaud, Marco Davila, Paul Love, James C Yang, Michael L Dustin, Grégoire Altan-Bonnet, Paul François, Naomi Taylor
Affiliations
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Department of Physics, McGill University, Montréal, QC, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.
- Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; CAMS Oxford Institute, University of Oxford, Oxford, UK.
- Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
- Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
- Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada; MILA Québec, Montréal, QC, Canada.
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Université de Montpellier, Institut de Génétique Moléculaire de Montpellier, Montpellier, France.
Abstract
Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHAT L8F/p53 R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.
MeSH
Cells, Fuzzy Logic, Neoplasms, Immunotherapy, Cell Biology, Therapeutics, Tissues, Robotics, Car-T Cell