CAR T Cells: Hitting the Pause Button

Researchers have found a way to temporarily halt the action of chimeric antigen receptor (CAR) T cells, if necessary, without compromising therapeutic efficacy. The strategy, involving the small-molecule inhibitor dasatinib (Sprycel; Bristol-Myers Squibb), shows preclinical promise and could eventually help mitigate the therapy's side effects (Sci Transl Med 2019;11:eaau5907).

CAR T-cell therapy “can't be controlled once it's in [a patient],” notes senior author Michael Hudecek, MD, of Universitätsklinikum Würzburg in Germany. The main adverse event, cytokine release syndrome (CRS), can be life-threatening and is primarily managed with tocilizumab (Actemra; Genentech) or high-dose corticosteroids. Whether to add a suicide gene to the CAR construct has elicited interest, but no approved CAR therapies include such “kill switches.”

“I thought it would be cool if, instead, we had a pharmacologic on/off switch to steer the function of CAR T cells,” Hudecek says, “which would mean interfering at the level of signal transmission.” To that end, the Würzburg team, led by first author Katrin Mestermann, PhD, screened a panel of tyrosine kinase inhibitors and landed on dasatinib. Approved for certain blood cancers and developed to target the BCR–ABL fusion protein, dasatinib also blocks another kinase, LCK. This prevents phosphorylation of CD3ζ and ZAP70, as well as the induction of NFAT, a key transcription factor in activated CAR T cells.

Given that all current CAR constructs contain a CD3ζ domain, Hudecek figured dasatinib “could be of universal relevance” in modulating this live therapy. In vitro, his group showed that CD19-targeting CAR T cells were effectively inhibited—in terms of cytolytic activity, cytokine secretion, and proliferation—with the drug.

Importantly, dasatinib's impact was reversible: CAR T cells regained function soon after drug removal, and their viability was unaffected. Similar results were obtained in a mouse model of lymphoma, and again, efficacy was not compromised.

As far as “remote control” options for CAR T-cell therapy go, dasatinib could be a good one to consider, says study coauthor Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY. “It acts rapidly, can be readily discontinued, and is already available.”

To investigate the drug's potential in alleviating CRS, Hudecek collaborated with Sadelain using a mouse model developed by the latter's team (Nat Med 2018;24:731–8). These mice, designed to develop acute, often fatal CRS upon receiving CAR T cells, fared much better if given dasatinib shortly after therapy infusion: At 48 hours, 70% were still alive compared with 25% in a control group.

Overall, “this is very timely work, and the science is sound,” says Marco Ruella, MD, of the University of Pennsylvania in Philadelphia, who was not involved in the research. The data do suggest that dasatinib is less effective at inhibiting actively proliferating CAR T cells, “as occurs in the clinic during CRS,” he points out. The timing of administration, then, “could be critical, and probably a preemptive approach would be more successful,” he adds. Sadelain agrees that “it may be important to give dasatinib early enough in the course of treatment to prevent CRS.”

Hudecek, too, points to research that has uncovered biomarkers to predict the risk of severe CRS following CAR T-cell therapy (Blood 2017;130:2295–306). “We could have a window of opportunity to intervene with these patients,” he says.

Directly comparing dasatinib with tocilizumab and corticosteroids in a future study would also be useful, Ruella thinks. “We'll better understand the actual potency of this approach and its relative effects—versus standard CRS medications—on CAR T-cell function and survival,” he says. –Alissa Poh

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