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PLASTIC RECONSTRUCTIVE AND REGENERATIVE SURGERY

Original article

Vol. 23 No. 4 (2025): Blood Transfusion 4-2025 (July-August)

The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia

Authors

Huiru Wang , Shanglong Feng , Yanliang Zhu , Yafeng Zhang , Ziwei Zhou , Zhigang Nian , Xueqin Lu , Peng Peng , Shu Wu , Li Zhou

Key words: acute myeloid leukemia, C-type lectin-like molecule-1, CD33, Chimeric antigen receptor, Leukemia stem cells.
Doi: 10.2450/BloodTransfus.786
Cellular therapy and regenerative medicine
Publication Date: 2024-08-06

Abstract

Background - Acute myeloid leukemia (AML) is characterized by high heterogeneity, poor long-term survival, and a propensity for relapse. Exceptional efficacy in treating recurrent or refractory B-lymphoid malignancies has been demonstrated by Chimeric antigen receptor T cells (CAR-T cells). Given the therapeutic potential of targeting both CD33 and C-type lectin-like molecule-1 (CLL1) in AML, the development of a dual-targeting CD33-CLL1 CAR-T cells assumes significant importance.

Materials and methods - The expressions of CD33 and CLL-1 antigens in peripheral blood cells and bone marrow cells from AML patients was assessed. Subsequently, a Chimeric Antigen Receptor (CAR) incorporating a dual-specific single-chain variable fragment targeting CLL1 and CD33 (CD33-CLL1-CAR-T) was engineered. The anti-tumor efficacy and potential side effects of CD33-CLL1-CAR-T cells were comprehensively investigated in both in vitro and in vivo settings.

Results - The constructed tandem CD33-CLL1 CAR-T exhibited potent cytotoxicity against leukemia cell lines and human primary AML cells in vitro. Co-cultivation of AML blasts with CD33-CLL1-CAR-T cells resulted in effective proliferation and the secretion of substantial quantities of GM-CSF and IFN-γ. Importantly, the impact of CD33-CLL1-CAR-T cells on normal hematopoietic stem cells was minimal, ensuring safety in vivo mouse models. Notably, significant anti-leukemic activity was observed in the mouse model, with CD33-CLL1-CAR-T cells leading to tumor eradication and prolonged survival.

Discussion - The tandem CD33-CLL1 CAR-T cells not only efficiently eliminated AML blasts but also exhibited low cytotoxicity toward normal hematopoietic stem cells (HSCs). These findings underscore the potential clinical applicability of the tandem CD33-CLL1 CAR-T cells as an effective and safe treatment strategy for AML, representing a noteworthy advancement in the field of CAR-T cells therapy.

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Authors

Huiru Wang Department of Blood Transfusion, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Shanglong Feng Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China; National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

Yanliang Zhu Nanjing Legend Biotechnology Co., Nanjing, China

Yafeng Zhang Nanjing Legend Biotechnology Co., Nanjing, China

Ziwei Zhou Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Zhigang Nian Institute of Immunology, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Xueqin Lu Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Peng Peng Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

Shu Wu Nanjing Legend Biotechnology Co., Nanjing, China

Li Zhou Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China; Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

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