Adoptive cell therapy including chimeric antigen receptor (CAR) T cells targeting CD19 has been approved by FDA to treat B cell-derived malignancies with remarkable success. The success has not yet been expanded to treating Acute Myeloid Leukemia (AML). We previously showed that a nanobody and single-chain fragment variable (scFv) CD13 (Nanobody)/TIM-3 (scFv) directed bispecific split CAR (bissCAR) T cells, while effective in eliminating AML in preclinical models, also caused substantial toxicity to human hematopoietic stem cells (HSCs) and other lineages. To maintain the bissCART specificity and efficacy, yet reduce toxicity to normal cells including HSCs, we generated new anti-TIM-3 nanobodies and constructed new cognate nanobodies-directed CD13/41BB and TIM3/CD3zeta nbiCARTs. The resultant nbiCARTs showed strong antitumor activity to CD13/TIM3 positive leukemic cells