Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia.

Chimeric antigen receptor (CAR) T cells have radically improved the treatment of B cell-derived malignancies by targeting CD19. The success has not yet expanded to treat acute myeloid leukemia (AML). We developed a Sequentially Tumor-Selected Antibody and Antigen Retrieval (STAR) system to rapidly isolate multiple nanobodies (Nbs) that preferentially bind AML cells and empower CAR T cells with anti-AML efficacy. STAR-isolated Nb157 specifically bound CD13, which is highly expressed in AML cells, and CD13 CAR T cells potently eliminated AML in vitro and in vivo. CAR T cells bispecific for CD13 and TIM3, which are upregulated in AML leukemia stem cells, eradicated patient-derived AML, with much reduced toxicity to human bone marrow stem cells and peripheral myeloid cells in mouse models, highlighting a promising approach for developing effective AML CAR T cell therapy.

Islet-specific Prmt5 excision leads to reduced insulin expression and glucose intolerance in mice.

Protein arginine methyltransferase 5 (PRMT5), a symmetric arginine methyltransferase, regulates cell functions by influencing gene transcription through posttranslational modification of histones and non-histone proteins. PRMT5 interacts with multiple partners including menin, which controls beta cell homeostasis. However, the role of Prmt5 in pancreatic islets, particularly in beta cells, remains unclear. A mouse model with an islet-specific knockout (KO) of the Prmt5 gene was generated, and the influence of the Prmt5 excision on beta cells was investigated via morphologic and functional studies. Beta cell function was evaluated by glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test. Beta cell proliferation was evaluated by immunostaining. Gene expression change was determined by real-time qPCR. Molecular mechanisms were investigated in beta cells in vitro and in vivo in Prmt5 KO mice. The results show that islet-specific KO of Prmt5 reduced expression of the insulin gene and impaired glucose tolerance and GSIS in vivo. The mechanistic study indicated that PRMT5 is involved in the regulation of insulin gene transcription, likely via histone methylation-related chromatin remodeling. The reduced expression of insulin in beta cells in the Prmt5 KO mice may contribute to impaired glucose tolerance (IGT) and deficient GSIS in the mouse model. These results will provide new insights into exploring novel strategies to treat diabetes caused by insulin insufficiency.