Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3K? Downregulation

We previously constructed a nanobody-based anti-CD38 chimeric antigen receptor T (CD38-CAR-T) cell efficiently against multiple myeloma. As CD38 is also expressed on most tumor cells of acute myeloid leukemia (AML), we wondered about its efficacy in treating AML. In this study, we demonstrated that our CD38-CAR-T cells effectively lysed CD38+ AML cell lines, including NB4, U937, HL-60, THP-1 with an E:T (effector/target cells) ratio of 1:8, and primary AML cells from patients with a low E:T ratio of 1:16. Moreover, recent studies showed that inhibition of PI3Kd could enhance CAR-T-cell efficacy. We constructed PI3Kd-downregulated CD38-CAR-T cells with a CD38-CAR lentiviral vector containing short hairpin RNA (shRNA) sequences against PI3Kd. CD38-CAR-T cells with PI3Kd downregulation maintained their antileukemia function against both AML cell lines and primary AML cells while reducing the release of IL-2, IFN-?, and TNF when co-culturing with AML cell lines. Both CD38-CAR-T and PI3Kd-downregulated CD38-CAR-T-cell therapy significantly improved the survival of AML mice, whereas the latter had an even better effect on survival. In summary, our study demonstrated that CD38-CAR-T cells had promising activity against AML, and PI3Kd downregulation in CD38-CAR-T cells could reduce some cytokines release without impairing their antileukemia function.

Automated summary

We found that CD38-CAR-T cells were effective against AML, and downregulation of PI3Kd in CD38-CAR-T cells reduced cytokine release without impairing their anti-leukemia function. The study demonstrated the promising activity of CD38-CAR-T cells against AML and the potential to enhance their efficacy through PI3Kd downregulation.