CAR-T cell therapies that transform a patient’s own immune cells into cancer-killing weapons have been hailed as breakthroughs for treating some blood cancers. But managing cytokine release syndrome (CRS), the most common acute side effect associated with CAR-T cells, is still a challenge. A team of researchers in Germany has now found a possible solution in Bristol-Myers Squibb’s leukemia drug Sprycel.
Scientists at the University Hospital Würzburg showed that Sprycel can act quickly to put a temporary pause on CAR-T cells in mice, sparing some of the animals from the potentially fatal CRS. The findings, published in the journal Science Translational Medicine, suggest the drug could be used as an “on/off switch” for CAR-T cells, they say.
CRS is triggered by the release of inflammatory molecules from both CAR-T cells and innate immune cells. Currently available methods to rein in CRS either cannot completely control CAR-T cell function or can kill the anti-cancer effect for good.
CAR-T therapies contain CD8+ killer T cells and CD4+ helper T cells. In lab dishes, the University Hospital Würzburg researchers found that Sprycel could lock these two types of CAR-T cells in an inactive state by interfering with an enzyme called LCK, thereby preventing them from producing inflammatory molecules that cause CRS. The blockade lasted for seven days, with no signs of the effect wearing off, according to the team.
But can the off switch be reversed? The researchers carefully removed Sprycel from cell cultures and discovered that the CAR-T cells rapidly switched back on and started killing target cells. Within seven hours, CAR-T cells had regained their full power at breaking down target cells, the team reported.
The study’s senior author Michael Hudecek and colleagues compared Sprycel’s inhibitory effect with that of dexamethasone, a steroid that’s commonly used to control CAR-T cells by systemic immunosuppression. They showed that Sprycel could immediately put a complete halt to CAR-T activities, whereas dexamethasone acted more slowly and exhibited only partial inhibition.
To verify the findings, the German team also used a mouse model of lymphoma. Giving Sprycel to a subgroup of mice soon after CAR-T infusion prevented fatal CRS in 70% of rodents, while only 25% of untreated mice survived CRS, the team found. After Sprycel was discontinued, CAR-T cells also quickly resumed their anti-lymphoma activity.
CAR-T therapies are being examined for their potential beyond blood cancer, so containing potentially life-threatening CRS will be vital. Researchers led by the University of Southern California recently used a CAR (chimeric antigen receptor) variant that they say produced lower levels of cytokines. And researchers from San Raffaele Hospital in Italy and Memorial Sloan Kettering in New York found that using the Amgen-developed rheumatoid arthritis treatment Kineret could be an effective way to control CRS.
Now Sprycel might also serve as a good emergency drug to quickly shut down CRS in patients receiving CAR-T infusions. Its rapid onset and complete but reversible control over CAR-T cells makes it an attractive option because there are multiple clinical scenarios where CRS is only transient, Hudecek’s team said in the study.
What’s more, using Sprycel at defined intervals might also serve a second function: protecting CAR-T cells becoming exhausted and ineffective. When the cells are engaged in chronic signaling, that can cause fatigue that limits their cancer-killing power. Sprycel could prevent T-cell exhaustion by giving the cells a short break, the researchers suggest.