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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for most of acute myeloid leukemia (AML) patients. But relapse remains the leading cause of mortality after transplant. Ex vivo expanded allogeneic CD4- and CD8- double negative T cells (allo-DNTs) effectively target AML cells without attacking normal tissues in preclinical models. In this first-in-human phase I/IIa trial, twelve patients with relapsed AML after allo-HSCT were treated with allo-DNTs. Nine patients had hematological relapse, 2 with molecular relapse, and 1 had both molecular and extramedullary relapse. The median times from transplant to relapse and relapse to DNT therapy were 10 months (3-18 months) and 4.7 months (1.75-11.7 months), respectively. At the time of DNT-treatment, 11/12 patients had active or residual disease. After lymphodepleting preconditioning, patients received allo-DNTs in three dose cohorts (5x107-4x108/kg). None of the patients developed graft-versus-host disease or > grade 2 DNT treatment-related toxicity; hence, the maximum tolerated dose was not reached. One patient withdrew from this trial. The initial response was observed in 7 out of 11 patients, where 4 patients achieved complete remission (CR), 2 achieved CR with incomplete hematologic recovery, and 1 achieved partial remission. Five patients remain alive and 4 are in continuing CR 374 to 609 days after DNT-treatment. The predicted 1-year overall survival after DNT treatment is 45.5% (95% CI, 16.7%-70.7%). Collectively, the study supports the feasibility, safety, and potential efficacy of allo-DNTs as a new treatment option for patients with relapsing/relapsed AML after allo-HSCT. Trial Registration: The trial was registered on the Chinese Clinical Trial Registry (ChiCTR-IPR-1900022795). Funding: This work was supported by the National Natural Science Foundation of China (grant # 81670165), International Cooperation Projects in Anhui Province (grant # 1804b06020352), the Fundamental Research Funds for the Central Universities (grants # WK9110000001 and WK9110000060), the Canadian Cancer Society Impact Grant (grant # 704121), Canadian Institutes of Health Research (grant # 419699), the Leukemia & Lymphoma Society (grant #R6509-18) and WYZE Biotech Inc. Declaration of Interest: LZ is a co-inventor on several DNT cell technology related patents and intellectual properties (IPs), received a grant and consulting fees from WYZE Biotech Co. Ltd. WYZE Biotech Co. Ltd licensed the Chinese right for one of the patents; and LZ owns shares in WYZE Biotech Co. Ltd.. LY, JL, and ADS are co-inventor on DNT cell technology related patents/IPs. LY, ZX, MW and PT own shares in WYZE Biotech Co., Ltd and are employees of WYZE Biotech Co., Ltd. MISSING REMAINING AUTHORS Ethical Approval: This study protocol was approved by Chinese Ethics Committee of Registering Clinical Trials. Written informed consent was obtained from all the patients or guardians in accordance with the Declaration of Helsinki.