Nian Z, Zheng X, Dou Y, et al. Rapamycin Pretreatment Rescues the Bone Marrow AML Cell Elimination Capacity of CAR-T Cells. Clinical Cancer Research. 2021; (doi: 10.1158/1078-0432.CCR-21-0452).
The limited success of chimeric antigen receptor (CAR) T therapy against acute myeloid leukemia (AML) observed in clinical trials may be due in part to inadequate eradication of AML cells in bone marrow — a shortcoming that may be solved with rapamycin pretreatment, according to new research. Researchers determined that CAR-T cells targeting Epithelial cell adhesion molecule (EpCAM) did demonstrate killing activity against AML cells elsewhere, but infiltration into the bone marrow was hampered by aberrantly activated mTORC1 signaling in CAR-T cells. The signaling also reduced levels of CXCR4, notable for its role in enhancing the bone marrow infiltration capacity of EpCAM CAR-T cells. Investigators found that mTORC1 activity was attenuated with rapamycin pretreatment of EpCAM CAR-T cells, thus increasing their ability to infiltrate the bone marrow and wipe out more AML cells. This pretreatment strategy, validated in xenograft murine models of leukemia, is also simple to implement, the study authors note.