Journal Article Review Research Support, Non-U.S. Gov't Epublish 11 citations
PubMed: 38090558 DOI: 10.3389/fimmu.2023.1321596
Fine-tuning the antigen sensitivity of CAR T cells: emerging strategies and current challenges.
Front Immunol 14:1321596
Authors: Dennis Christoph Harrer, Sin-Syue Li, Marcell Kaljanac, Markus Barden, Hong Pan, Hinrich Abken
Affiliations
- Deptartment of Hematology and Internal Oncology, University Hospital Regensburg, Regensburg, Germany.
- Leibniz Institute for Immunotherapy, Division of Genetic Immunotherapy, Chair Genetic Immunotherapy, University Regensburg, Regensburg, Germany.
- Division of Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract
Chimeric antigen receptor (CAR) T cells are "living drugs" that specifically recognize their target antigen through an antibody-derived binding domain resulting in T cell activation, expansion, and destruction of cognate target cells. The FDA/EMA approval of CAR T cells for the treatment of B cell malignancies established CAR T cell therapy as an emerging pillar of modern immunotherapy. However, nearly every second patient undergoing CAR T cell therapy is suffering from disease relapse within the first two years which is thought to be due to downregulation or loss of the CAR target antigen on cancer cells, along with decreased functional capacities known as T cell exhaustion. Antigen downregulation below CAR activation threshold leaves the T cell silent, rendering CAR T cell therapy ineffective. With the application of CAR T cells for the treatment of a growing number of malignant diseases, particularly solid tumors, there is a need for augmenting CAR sensitivity to target antigen present at low densities on cancer cells. Here, we discuss upcoming strategies and current challenges in designing CARs for recognition of antigen low cancer cells, aiming at augmenting sensitivity and finally therapeutic efficacy while reducing the risk of tumor relapse.
MeSH
Immune System Diseases, Cells, Therapeutics, Neoplasms, T-Lymphocytes, B-Lymphocytes, Down-Regulation, Car-T Cell
Cited by
- Preclinical evaluation of antigen-sensitive B7-H3-targeting nanobody-based CAR-T cells in glioblastoma cautions for on-target, off-tumor toxicity. J Immunother Cancer, 2024
- Harnessing antibody-mediated recognition of the intracellular proteome with T cell receptor-like specificity. Front Immunol, 2024
- Tailoring CAR surface density and dynamics to improve CAR-T cell therapy. J Immunother Cancer, 2025
- Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies. Front Immunol, 2024
- Affinity-matured CD72-targeting Nanobody CAR T-cells Enhance Elimination of Antigen-Low B-cell Malignancies. bioRxiv, 2025