Rapamycin Pre-Treatment of CAR T Cells “May Enhance Therapeutic Efficacy Against AML”

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A recently published article on CAR T cells in patients with acute myeloid leukemia is featured by CancerNetwork's Strategic Alliance Partner ASTCT.

The following was recently published in ASTCT’s Nucleus Plus: Emerging CAR T publication.

Pretreatment of CAR T cells with rapamycin during ex vivo expansion “dramatically enhanced” the cells’ ability to infiltrate bone marrow and promoted the elimination of acute myeloid leukemia (AML) cells, Chinese researchers report in a study published in Clinical Cancer Research in July.

Trials to date have shown only limited efficacy of CAR T-cell therapy in the treatment of AML.

This study, by researchers at the University of Science and Technology of China, suggest that the cause of this limited efficacy may be that CAR-T cells downregulate the expression of CXCR4 during ex vivo expansion, reducing the cells’ in vivo capacity to migrate to bone marrow and weakening their ability to eliminate AML cells there.

“Stimulating T cells with anti-CD3/CD28 antibodies and tonic CAR signaling both strengthen the activation of the mTOR signaling, which causes downregulation of CXCR4,” senior author Haiming Wei and colleagues write. “We found that attenuating mTORC1 activation with rapamycin can overcome this artifact of ex vivo CAR-T cell manipulation, promoting CXCR4 accumulation and thereby increasing the bone marrow migration capacity of CAR-T cells. Ultimately, the rapamycin-pretreated CAR-T cells have an enhanced therapeutic efficacy against AML.”

Rapamycin pretreatment can enhance the ability of both EpCAM CAR-T cells and CD33 CAR-T cells to eliminate bone marrow AML cells, the authors write, suggesting that “this pretreatment strategy is apparently suitable for improving the bone marrow AML elimination capacity of CAR-T cells engineered to target a variety of AML antigens.” They conclude: “Overall, our study illustrates an easy-to-implement strategy that strongly enhances the bone marrow leukemia cell elimination capacity of CAR-T cells and provides a basis for a planned clinical trial using rapamycin pretreated CAR-T cell against AML.”

Reference

Nian Z, Zheng X, Dou Y, et al. Rapamycin pretreatment rescues the bone marrow AML cell elimination capacity of CAR-T cells. Clin Cancer Res. Published online July 7, 2021. doi:10.1158/1078-0432.CCR-21-0452