Research ArticleCancer

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

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaau5907
DOI: 10.1126/scitranslmed.aau5907

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Putting CAR T cells in idle

Chimeric antigen receptor, or CAR, T cells can be an effective cell therapy for cancer. Unfortunately, this immunotherapy has its risks, and excessive activation of CAR T cells can occasionally cause severe, even lethal, toxicity. There are some existing approaches to suppressing overactive CAR T cells, but these are generally single-use methods that kill the CAR T cells and thereby abrogate both their toxicity and their antitumor effects. In contrast, Mestermann et al. identified dasatinib as a drug that can temporarily inactivate CAR T cells to help reduce acute toxicity, allowing the T cells to recover their antitumor effects after the drug is withdrawn.

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.

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