Mechanisms and strategies for safe chimeric antigen receptor T‐cell activity control

  • Sophia Stock
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Anna‐Kristina Klüver
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Luisa Fertig
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Vivien D. Menkhoff
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Marion Subklewe
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Stefan Endres
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany
  • Sebastian Kobold
    Division of Clinical Pharmacology, Department of Medicine IV LMU University Hospital, Ludwig‐Maximilians‐Universität München (LMU) Munich Germany

抄録

<jats:title>Abstract</jats:title><jats:p>The clinical application of chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed the treatment options for terminally ill patients with defined blood‐borne cancer types. However, CAR T‐cell therapy can lead to severe therapy‐associated toxicities including CAR‐related hematotoxicity, ON‐target OFF‐tumor toxicity, cytokine release syndrome (CRS) or immune effector cell‐associated neurotoxicity syndrome (ICANS). Just as CAR T‐cell therapy has evolved regarding receptor design, gene transfer systems and production protocols, the management of side effects has also improved. However, because of measures taken to abrogate adverse events, CAR T‐cell viability and persistence might be impaired before complete remission can be achieved. This has fueled efforts for the development of extrinsic and intrinsic strategies for better control of CAR T‐cell activity. These approaches can mediate a reversible resting state or irreversible T‐cell elimination, depending on the route chosen. Control can be passive or active. By combination of CAR T‐cells with T‐cell inhibiting compounds, pharmacologic control, mostly independent of the CAR construct design used, can be achieved. Other strategies involve the genetic modification of T‐cells or further development of the CAR construct by integration of molecular ON/OFF switches such as suicide genes. Alternatively, CAR T‐cell activity can be regulated intracellularly through a self‐regulation function or extracellularly through titration of a CAR adaptor or of a priming small molecule. In this work, we review the current strategies and mechanisms to control activity of CAR T‐cells reversibly or irreversibly for preventing and for managing therapy‐associated toxicities.</jats:p>

収録刊行物

被引用文献 (1)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ