Engineering TCR-controlled fuzzy logic into CAR T cells enhances therapeutic specificity.

Journal: Cell
PMID: 40220754

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/p53) 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.

Authors

  • Taisuke Kondo
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • François X P Bourassa
    Department of Physics, McGill University, Montréal, QC, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC, Canada.
  • Sooraj Achar
    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.
  • Justyn DuSold
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Pablo F Céspedes
    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.
  • Makoto Ando
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Alka Dwivedi
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Josquin Moraly
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Christopher Chien
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Saliha Majdoul
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Adam L Kenet
    Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Madison Wahlsten
    Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Audun Kvalvaag
    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.
  • Edward Jenkins
    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
  • Sanghyun P Kim
    Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Catherine M Ade
    Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Zhiya Yu
    Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Guillaume Gaud
    Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • Marco Davila
    Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • Paul Love
    Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
  • James C Yang
    Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • Michael L Dustin
    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
  • Grégoire Altan-Bonnet
    Immunodynamics Group, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
  • Paul François
    Physics Department, McGill University, Montreal, QC H3A2T8, Canada.
  • Naomi Taylor
    Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Université de Montpellier, Institut de Génétique Moléculaire de Montpellier, Montpellier, France. Electronic address: taylorn4@mail.nih.gov.

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