Patient Death Prompts Pause in 2seventy bio's Trial for Acute Myeloid Leukemia CAR-T

Seattle Children’s has paused the phase 1 PLAT-08 clinical trial (NCT05105152) evaluating 2seventy bio’s SC-DARIC33, an investigational CD33-directed chimeric antigen receptor T-cell (CAR-T) therapy intended to treat acute myeloid leukemia (AML), following the death of the first patient treated at the study’s second dose level (5x10⁶ SC-DARIC33 T-cells/kg).^1,2

Seattle Children’s and 2seventy bio, which are collaborating on the development of SC-DARIC33, are currently investigating the cause of the grade 5 serious adverse event (SAE) which lead to the patient’s death and the potential for its relation to SC-DARIC33. 2seventy stated that the FDA has been notified about the pause, which was required as per the clinical study protocol stopping rules.

“Importantly, I’d like to offer that our thoughts are with the family during this time,” Steve Bernstein, MD, the chief medical officer of 2seventy bio, said in a statement.¹ “The safety of every patient who participates in our studies or is treated with our therapies is the utmost priority for us, and we are in communication with FDA while we assess the data surrounding this SAE, and the potential next steps for the study."

SC-DARIC33 uses the company’s Dimerizing Agent Regulated Immunoreceptor Complex (DARIC) T-cell platform, which is intended to allow for regulation of CAR T-cell activity based on the presence of rapamycin.² The first-in-human trial PLAT-08 is evaluating SC-DARIC33 in patients aged 30 years or younger whose disease is in its first early relapse, its first relapse refractory to reinduction therapy, or a second or later relapse. Results from the patients treated at the trial’s first dose level (1x10⁶ SC-DARIC33 T-cells/kg), as of March 17, 2023, were presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California, by Jacob Appelbaum, MD, PhD, senior research fellow, Fred Hutch Cancer Center, and physician and acting instructor, Division of Hematology, University of Washington School of Medicine. At the time, the company reported that infusions of SC-DARIC33 in these 3 patients were generally well-tolerated and that there had been no dose-limiting toxicities. Expansion of SC-DARIC33 cells in the peripheral blood was reported in 1 of the patients. Furthermore, a significant transient decrease in CD33 leukemic burden, associated with the expansion, was observed in this patient’s blood.

CGTLive™ spoke to Appelbaum at ASGCT's 2023 meeting about SC-DARIC33 and the data he presented at the conference. He discussed the potential advantages of a regulated CAR strategy in patients with AML and plans for further research.

“One of the key challenges in AML is that the antigens that are most commonly targeted are expressed on stem cell progenitors,” Appelbaum said. “And so, if those cells are eliminated, the blood cell counts in those patients will decrease, and that presents a very serious infectious risk. So, 1 question is, can we eliminate that risk through regulation, i.e., turning the CAR T-cells on and off? One of the things that we're focused on is a platform where we can do that with a small molecule drug, in this case, rapamycin. So, when rapamycin is present, the CAR T-cells are on and when rapamycin is not present, the CAR T-cells are off.”

REFERENCES
1. 2seventy bio announces clinical study pause of PLAT-08 trial of SC-DARIC33 in acute myeloid leukemia. News release. 2seventy bio, Inc. June 14, 2023. Accessed June 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-announces-clinical-study-pause-plat-08-trial-sc
2. 2seventy bio presents late-breaking results for SC-DARIC33, an investigational CD33-targeting CAR T in pediatric and young adults with relapsed or refractory acute myeloid leukemia. News release. 2seventy bio, Inc. May 19, 2023. Accessed June 14, 2023. https://ir.2seventybio.com/news-releases/news-release-details/2seventy-bio-presents-late-breaking-results-sc-daric33