The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells Journal Article

Authors: Mestermann, K.; Giavridis, T.; Weber, J.; Rydzek, J.; Frenz, S.; Nerreter, T.; Mades, A.; Sadelain, M.; Einsele, H.; Hudecek, M.
Article Title: The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells
Abstract: Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require technologies to enable physicians (and patients) to maintain control over the infused cell product. Here, we demonstrate that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK) and thereby inhibits phosphorylation of CD3ζ and ζ-chain of T cell receptor-associated protein kinase 70 kDa (ZAP70), ablating signaling in CAR constructs containing either CD28-CD3ζ or 4-1BB-CD3ζ activation modules. As a consequence, dasatinib induces a function-off state in CD8+ and CD4+ CAR T cells that is of immediate onset and can be sustained for several days without affecting T cell viability. We show that treatment with dasatinib halts cytolytic activity, cytokine production, and proliferation of CAR T cells in vitro and in vivo. The dose of dasatinib can be titrated to achieve partial or complete inhibition of CAR T cell function. Upon discontinuation of dasatinib, the inhibitory effect is rapidly and completely reversed, and CAR T cells resume their antitumor function. The favorable pharmacodynamic attributes of dasatinib can be exploited to steer the activity of CAR T cells in "function-on-off-on" sequences in real time. In a mouse model of cytokine release syndrome (CRS), we demonstrated that a short treatment course of dasatinib, administered early after CAR T cell infusion, protects a proportion of mice from otherwise fatal CRS. Our data introduce dasatinib as a broadly applicable pharmacologic on/off switch for CAR T cells. © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Keywords: signal transduction; controlled study; protein phosphorylation; human cell; drug withdrawal; nonhuman; treatment duration; protein function; cd3 antigen; cd8+ t lymphocyte; cell proliferation; animal cell; mouse; cell viability; cell function; multiple cycle treatment; animal experiment; animal model; dexamethasone; in vivo study; antineoplastic activity; in vitro study; dasatinib; cd4+ t lymphocyte; cytokine production; drug dose titration; cd28 antigen; protein kinase lck; protein kinase zap 70; cytokine release syndrome; pharmacological parameters; human; female; priority journal; article; chimeric antigen receptor immunotherapy; tumor necrosis factor receptor superfamily member 9
Journal Title: Science Translational Medicine
Volume: 11
Issue: 499
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2019-07-03
Start Page: aau5907
Language: English
DOI: 10.1126/scitranslmed.aau5907
PUBMED: 31270272
PROVIDER: scopus
PMCID: PMC7523030
Notes: Article -- Source: Scopus
Citation Impact
MSK Authors
  1. Michel W J Sadelain
    502 Sadelain