08.17.21

Rapamycin pretreatment strategy enhances the anti-AML efficacy of CAR T cells

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).

New research suggests that a pretreatment strategy involving rapamycin boosts the efficacy of chimeric antigen receptor (CAR) T cells against acute myeloid leukemia (AML). Seeking to identify potential causes of the reported limited efficacy of CAR T treatments against AML, researchers produced CAR T cells targeting Epithelial cell adhesion molecule (EpCAM) and assessed their ability to destroy AML cells. The effects of modulating mTORC1 and mTORC2 signaling in CAR T cells on CXCR4 levels were studied, as was the impact of rapamycin pretreatment of EpCAM CAR T cells and CD33 CAR T cells in leukemia xenograft mouse models. Although EpCAM CAR T cells were found to kill AML cells, they did not eliminate AML cells in bone marrow. Further study noted a connection between reduced bone marrow infiltration and reduced levels of the rapamycin target CXCR4 and aberrantly activated mTORC1 signaling in CAR T cells. Attenuation of mTORC1 activity with rapamycin pretreatment increased the CAR T cells' ability to infiltrate bone marrow and more effectively eliminated AML cells in the mouse models. Knockdown experiments with CXCR4 demonstrated that it plays a role in the increased bone marrow infiltration capacity of EpCAM CAR T cells and the reduction in bone marrow AML cells.

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