Effective Killing of Acute Myeloid Leukemia by TIM-3 Targeted Chimeric Antigen Receptor T Cells.

Autor:	Lee WS; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Ye Z; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Cheung AMS; Department of Haematology, Singapore General Hospital, Singapore., Goh YPS; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Oh HLJ; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Rajarethinam R; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore., Yeo SP; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Soh MK; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore., Chan EHL; Department of Haematology-Oncology, National University Health Systems, Singapore., Tan LK; Department of Haematology-Oncology, National University Cancer Institute, Singapore.; Department of Laboratory Medicine, National University Hospital, Singapore., Tan SY; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.; Department of Pathology, National University Hospital, National University Health System, Singapore.; Department of Pathology, Yong Loo Lin School of Medicine, Singapore., Chuah C; Department of Haematology, Singapore General Hospital, Singapore.; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore., Chng WJ; Department of Haematology-Oncology, National University Health Systems, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Connolly JE; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.; Institute of Biomedical Studies, Baylor University, Waco., Wang CI; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore. Wang_Chengi@immunol.a-star.edu.sg.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Sep; Vol. 20 (9), pp. 1702-1712. Date of Electronic Publication: 2021 Jun 22.
DOI:	10.1158/1535-7163.MCT-20-0155
Abstrakt:	Acute myeloid leukemia (AML) is an aggressive disease with poor outcomes, overwhelmingly due to relapse. Minimal residual disease (MRD), defined as the persistence of leukemic cells after chemotherapy treatment, is thought to be the major cause of relapse. The origins of relapse in AML have been traced to rare therapy-resistant leukemic stem cells (LSCs) that are already present at diagnosis. Effective treatment strategies for long-term remission are lacking, as it has been difficult to eliminate LSCs with conventional therapy. Here, we proposed a new approach based on the chimeric antigen receptor (CAR)-directed T lymphocytes, targeting T-cell immunoglobulin, and mucin domain 3 (TIM-3) to treat MRD in patients with AML. TIM-3 is selected as the target because it is highly expressed on AML blasts and LSCs in most subtypes regardless of the patient's genetic characteristics and treatment course. Moreover, it is absent in the normal hematopoietic stem cells, granulocytes, naïve lymphocytes, and most normal nonhematopoietic tissues. Using a naïve human Fab phage display library, we isolated an anti-human TIM-3 antibody and designed a second-generation anti-TIM-3. Our anti-TIM-3 CAR T cells exhibit potent antileukemic activity against AML cell lines and primary AML blasts, and in the mouse models. More importantly, we demonstrate efficient killing of the primary LSCs directly isolated from the patients. Hence, eradication of the LSCs present in the MRD by anti-TIM-3 CAR T-cell therapy following the first-line treatment may improve the clinical outcomes of patients with AML. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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