CD33-targeted DARIC chimeric83 immunoreceptor targets AML with rapamycin
Ng BD, Rajagopalan A, Kousa AI, et al. IL-18-Secreting Multi-Antigen Targeting CAR T-CellsAppelbaum J, Price AE, Oda K, et al. Drug-Regulated CD33-Targeted CAR T Cells Control AML Using Clinically Optimized Rapamycin Dosing. Journal of Clinical Investigation. 2024; (doi: 10.1172/JCI162593).
In the setting of CD33+ acute myeloid leukemia, scientists achieved disease control using chimeric antigen receptor (CAR) T cells regulated by rapamycin. Dimerization agent regulated immunoreceptor complex (DARIC33) - a fully human, rapamycin-regulated drug product that targets CD33+ tumors - activated T cell effector functions, including cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity — in the presence of even low doses of rapamycin. Regulated DARIC33 cells also demonstrated high sensitivity to the target antigen, yet did not interfere with CD34+ stem cell colony formation. Exposure to and withdrawal from the drug served as a switch to turn effector function control on and off. The investigators identified rapamycin concentration thresholds for those transitions, along with a clinically appropriate dosing schedule. Based on the preclinical work, a Phase I study is now underway. Preliminary trial findings to date support rapamycin-regulated T cell activation and anti-tumor efficacy.