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Objectives: The treatment of refractory and recurrent acute myeloid leukaemia (AML) is still a challenge with poor response rates and short survival times. In an attempt to solve this problem, we constructed a tandem bispecific chimeric antigen receptor (CAR) targeting CD123 and C‐type lectin‐like molecule 1 (CLL‐1), two different AML antigens, and verified its cytotoxic effects in vitro. Methods: We established and cultured K562 cell lines expressing both CD123 and CLL1 antigens. Single‐target CAR‐T cells specific to CD123 and CLL1 were engineered, alongside tandem CD123/CLL1 bispecific CAR‐T cells. Flow cytometry was used to determine cell phenotypes, transfection efficiencies, cytokine release, and CAR‐T‐cell proliferation, and an lactate dehydrogenase assay was used to detect the cytotoxicity of CD123/CLL‐1 bispecific tandem CAR‐T cells in vitro. Results: Two types of tandem CAR‐T cells exhibited significant killing effects on CLL‐1 + CD123+ leukaemia cell lines and primary AML tumour cells. The killing efficiency of tandem CAR‐T cells in the case of single antigen expression is comparable to that of single target CAR‐T cells. When faced with dual target tumour cells, dual target CAR‐T cells significantly surpass single target CAR‐T cells. CD123/CLL‐1 CAR‐T cells in tandem targeted and killed CD123‐ and CLL‐1‐positive leukaemia cell lines and released a large number of cytokines. Conclusions: CD123/CLL‐1 CAR‐T cells in tandem can simultaneously target CD123 and CLL‐1 on AML cells, demonstrating a significant ability to kill single antigens and multi‐target tumour cells. This suggests that CD123/CLL‐1 CAR‐T cells exhibit significant advantages in the expression of multiple antigens in a wide range of target cells, which may help overcome the challenges posed by tumour heterogeneity and evasion mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To investigate the efficacy and safety of venetoclax (VEN) combined with demethylating agents (HMA) in the treatment of relapsed/refractory acute myeloid leukemia (R/R AML)., Methods: The clinical data of 26 adult R/R AML patients who received the combination of VEN with azacitidine (AZA) or decitabine (DAC) in Huai'an Second People's Hospital from February 2019 to November 2021 were retrospectively analyzed. The treatment response, adverse events as well as survival were observed, and the factors of influencing the efficacy and survival were explored., Results: The overall response rate (ORR) of 26 patients was 57.7% (15 cases), including 13 cases of complete response (CR) and CR with incomplete count recovery (CRi) and 2 cases of partial response (PR). Among the 13 patients who got CR/CRi, 7 cases achieved CRm (minimal residual disease negative CR) and 6 cases did not, with statistically significant differences in overall survival (OS) and event-free survival (EFS) between the two groups (P=0.044, 0.036). The median OS of all the patients was 6.6 (0.5-15.6) months, and median EFS was 3.4 (0.5-9.9) months. There were 13 patients in the relapse group and refractory group, respectively, with response rate of 84.6% and 30.8% (P=0.015). The survival analysis showed that the relapse group had a better OS than the refractory group (P=0.026), but there was no significant difference in EFS (P=0.069). Sixteen patients who treated for 1-2 cycles and 10 patients who treated for more than 3 cycles achieved response rates of 37.5% and 90.0%, respectively (P=0.014), and patients treated for more cycles had superior OS and EFS (both P<0.01). Adverse effects were mainly bone marrow suppression, complicated by various degrees of infection, bleeding, and gastrointestinal discomfort was common, but these could be all tolerated by patients., Conclusion: VEN combined with HMA is an effective salvage therapy for patients with R/R AML and is well tolerated by patients. Achieving minimal residual disease negativity is able to improve long-term survival of patients.