Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia

Mayumi Sugita, Roman Galetto, Hongliang Zong, Nathan Ewing-Crystal, Vicenta Trujillo-Alonso, Nuria Mencia-Trinchant, Winnie Yip, Stephanie Filipe, Celine Lebuhotel, Agnès Gouble, Duane C. Hassane, Julianne Smith, Gail J. Roboz () and Monica L. Guzman ()
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Mayumi Sugita: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Roman Galetto: Cellectis SA
Hongliang Zong: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Nathan Ewing-Crystal: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Vicenta Trujillo-Alonso: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Nuria Mencia-Trinchant: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Winnie Yip: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Stephanie Filipe: Cellectis SA
Celine Lebuhotel: Cellectis SA
Agnès Gouble: Cellectis SA
Duane C. Hassane: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Julianne Smith: Cellectis SA
Gail J. Roboz: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College
Monica L. Guzman: Division of Hematology and Oncology, Department of Medicine. Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαβneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.

Date: 2022
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DOI: 10.1038/s41467-022-29668-9

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