Death triggers pause of 2seventy CAR-T cell therapy leukemia trial

Investigators have paused an early-phase trial of 2seventy bio’s CD33-targeted CAR-T cell therapy after a patient died. The acute myeloid leukemia (AML) patient was the first person treated in the second dose cohort of the phase 1 clinical trial.

2seventy, bluebird bio’s oncology spinoff, designed the cell therapy to address safety problems that have held back the application of the modality to AML. The cancer cells express multiple surface antigens, but they are also found on healthy myeloid lineage and progenitor cells, raising the question of how to take out AML without causing intolerable side effects.   

The answer, in 2seventy’s eyes, lies in a CAR architecture that physicians can turn on and off with another drug, namely rapamycin. Giving the drug at non-immunosuppressive dose levels activates the CAR-T cell therapy. When rapamycin is absent, the therapy is inactive, allowing hematopoietic cells to recover. 

That’s the theory. 2seventy began putting it to the test last year, when Seattle Children’s dosed the first patient with the biotech's CAR-T, dubbed SC-DARIC33. The early signs looked good, with investigators reporting last month that infusions at the first dose level were generally well tolerated by the first three patients. None of the patients suffered dose-limiting toxicities. 

Now, the death of the first patient treated at the second dose level has raised doubts about the program. Little is known publicly at this stage, with 2seventy’s statement devoid of details about how the patient died. The root cause of the adverse event and its potential link to SC-DARIC33 are being investigated. 

Seattle Children’s responded to the death by pausing the study and notifying the FDA. Steve Bernstein, M.D., chief medical officer at 2seventy, added that the company is in communication with the FDA while it reviews the data and the potential next steps for the study. A significant setback to SC-DARIC33 would leave 2seventy focused on its non-Hodgkin lymphoma cell therapy bbT369 as well as its Abecma partnership with Bristol Myers Squibb.

The details of the death could have implications for 2seventy’s wider strategy. The paused clinical trial is the first time 2seventy has tested its drug-regulated CAR-T cell platform in humans, and the biotech was looking to the study to lay the foundations for future work on CD33 and solid tumor targets.