Lowering mTORC1 Drives CAR T-Cells Home in Acute Myeloid Leukemia

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Acute myeloid leukemia (AML) remains a challenge for cellular therapies.
• Chimeric antigen receptor (CAR) T-cells show promise but face efficacy limitations in AML.
• mTOR complex 1 activation has been shown to downregulate CXCR4, hindering CAR T-cell infiltration in AML bone marrow.

Purpose of the Study:

• To investigate the impact of abrogating mTOR signaling on CAR T-cell function in AML.
• To determine if modulating CXCR4 expression can enhance CAR T-cell efficacy against AML.

Main Methods:

• Utilized IL2-mediated ex vivo expansion of EpCAM-targeting CAR T-cells for AML.
• Administered mTOR inhibitors cotreatment during the expansion phase.
• Assessed CXCR4 expression levels on CAR T-cells.
• Evaluated CAR T-cell migration to the bone marrow in an AML model.
• Quantified AML elimination by CAR T-cells.

Main Results:

• Abrogating mTOR signaling upregulated CXCR4 expression on CAR T-cells.
• Enhanced CXCR4 expression led to improved CAR T-cell migration into the bone marrow.
• Cotreatment with mTOR inhibitors significantly bolstered the elimination of AML by CAR T-cells.

Conclusions:

• Targeting mTOR signaling is a viable strategy to enhance CAR T-cell therapy for AML.
• Upregulating CXCR4 expression via mTOR inhibition improves CAR T-cell homing and anti-leukemic activity.
• This approach offers a promising avenue for improving cellular therapy outcomes in AML.