Jacob Appelbaum, MD, PhD, on Investigating SC-DARIC33 and IL-15 for AML

“We wondered whether augmenting IL-15 could replace some of the circulating IL-15 that is lost following therapy. So, we designed a genetic module that we could incorporate in the lentivirus alongside the DARIC33 to provide that enhancement. So, it had 2 parts, it had a T-cell specific inducible promoter, and 1portion of the research that we did was to figure out how to design that promoter. And That promoter is specifically activated following T-cell stimulation. And the second part of it is this protein modification that enhances safety through restriction of activity to the IL-15 receptor α-expressing cells. Ultimately, by incorporating those 2 features along with DARIC33, we showed that we could reduce the dose of DARIC33 required to suppress AML growth in mice by at least 3-fold.”

Preliminary data from the phase 1 PLAT-08 clinical trial (NCT05105152) evaluating 2seventy bio’s SC-DARIC33 in patients with acute myeloid leukemia (AML) were presented at the American Society of Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, held May 16-20, in Los Angeles, California.¹ The data were from patients treated with 1 x 10⁶ SC-DARIC33 T cells/kg. Shortly after, in June 2023, Seattle Children’s announced that they had paused the trial following the death of the first patient treated at the study’s second dose level (5x10⁶ SC-DARIC33 T-cells/kg).²

SC-DARIC33 is an investigational CD33-directed chimeric antigen receptor T-cell (CAR-T) therapy activated by rapamycin that uses 2seventy’s Dimerizing Agent Regulated ImmunoReceptor Complex (DARICs) technology. At the time of the data presented at the ASGCT, SC-DARIC33 had displayed successful regulated activation in 3 patientstreated with 1 x 10⁶ SC-DARIC33 T cells/kg.

Data from the study were presented 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. CGTLive spoke with Appelbaum to learn more about his investigations with SC-DARIC33 and other promising research trends he observed at the ASGCT meeting.

Click here to read more coverage of ASGCT 2023.

REFERENCES

1. Appelbaum J, Cooper T, Annesley C, et al. first in human studies show activation of SC-DARIC33, a rapamycin-regulated anti-CD33 CAR t cell therapy, in patients with AML. Presented at: ASGCT 2023 Annual Meeting; May 16-20; Los Angeles, California.
2. 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