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PLASTIC RECONSTRUCTIVE AND REGENERATIVE SURGERY

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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