The tyrosine kinase inhibitor dasatinib was found to transiently inhibit CAR T-cell function in mice, suggesting applicability as an on-off control for CAR T-cell therapy, investigators report.
“In this study, we focused our efforts on evaluating dasatinib as a control drug for CAR T cells,” wrote Katrin Mestermann, PhD, of the University of Würzburg in Germany and colleagues in.
The researchers explored the pharmacological effects of dasatinib on CAR T-cell function using a mouse xenograft model. In this model, dasatinib was administered every 6 hours to sustain serum levels above a mandatory threshold to ensure human pharmacokinetic equivalence.
The team observed that dasatinib interferes with several cellular mechanisms that effect CAR T-cell activity, including inhibition of protein phosphorylation and cytokine secretion, among others.
Short-term administration of dasatinib was shown to not alter antilymphoma activity of CD19-CAR T cells, according to data from in vivo experiments.
In addition, upon cessation of dasatinib, CAR T-cell antitumor activity was rapidly restored, based on in vitro experiment data.
Dr. Mestermann and her colleagues also noted that the dose of dasatinib was titratable to attain either partial or complete inhibition of CAR T-cell activity. These effects could be maintained for several days without altering T-cell survival.
“A short treatment course of dasatinib, administered early after CAR T-cell infusion, protects a proportion of mice from otherwise fatal cytokine release syndrome,” the researchers wrote.
Cytokine release syndrome is the most frequently seen acute toxicity linked to CAR T-cell therapy, they explained.
“Further studies are warranted to determine whether dasatinib is also effective in clinical situations with established cytokine release syndrome,” they concluded.
The study was funded by the Cluster Biotechnologie Bayern and Free State of Bavaria, the German Cancer Aid, and the University of Würzburg. The authors reported financial affiliations with Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Takeda, and others.
SOURCE: Mestermann K et al. Sci Transl Med. 2019 Jul 3. .