Targeting CD123 in blastic plasmacytoid dendritic cell neoplasm using allogeneic anti-CD123 CAR T cells

Tianyu Cai, Agnès Gouble, Kathryn L. Black, Anna Skwarska, Ammar S. Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S. Neelapu, Andrew A. Lane, Hagop Kantarjian, Monica L. Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko and Marina Konopleva ()
Additional contact information
Tianyu Cai: The University of Texas MD Anderson Cancer Center
Agnès Gouble: Cellectis SA
Kathryn L. Black: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Anna Skwarska: The University of Texas MD Anderson Cancer Center
Ammar S. Naqvi: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Deanne Taylor: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Ming Zhao: The University of Texas MD Anderson Cancer Center
Qi Yuan: The University of Texas MD Anderson Cancer Center
Mayumi Sugita: Division of Hematology & Medical Oncology, Weill Cornell Medicine
Qi Zhang: The University of Texas MD Anderson Cancer Center
Roman Galetto: Cellectis SA
Stéphanie Filipe: Cellectis SA
Antonio Cavazos: The University of Texas MD Anderson Cancer Center
Lina Han: The University of Texas MD Anderson Cancer Center
Vinitha Kuruvilla: The University of Texas MD Anderson Cancer Center
Helen Ma: The University of Texas MD Anderson Cancer Center
Connie Weng: The University of Texas MD Anderson Cancer Center
Chang-Gong Liu: The University of MD Anderson Cancer Center
Xiuping Liu: The University of MD Anderson Cancer Center
Sergej Konoplev: The University of MD Anderson Cancer Center
Jun Gu: The University of Texas MD Anderson Cancer Center
Guilin Tang: The University of MD Anderson Cancer Center
Xiaoping Su: The University of Texas MD Anderson Cancer Center
Gheath Al-Atrash: The University of MD Anderson Cancer Center
Stefan Ciurea: The University of MD Anderson Cancer Center
Sattva S. Neelapu: The University of MD Anderson Cancer Center
Andrew A. Lane: Dana-Farber Cancer Institute
Hagop Kantarjian: The University of Texas MD Anderson Cancer Center
Monica L. Guzman: Division of Hematology & Medical Oncology, Weill Cornell Medicine
Naveen Pemmaraju: The University of Texas MD Anderson Cancer Center
Julianne Smith: Cellectis SA
Andrei Thomas-Tikhonenko: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Marina Konopleva: The University of Texas MD Anderson Cancer Center

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

Abstract: Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN® nucleases. In this study, we examine the antitumor activity of UCART123 in preclinical models of BPDCN. We report that UCART123 have selective antitumor activity against CD123-positive primary BPDCN samples (while sparing normal hematopoietic progenitor cells) in the in vitro cytotoxicity and T cell degranulation assays; supported by the increased secretion of IFNγ by UCART123 cells when cultured in the presence of BPDCN cells. UCART123 eradicate BPDCN and result in long-term disease-free survival in a subset of primary patient-derived BPDCN xenograft mouse models. One potential challenge of CD123 targeting therapies is the loss of CD123 antigen through diverse genetic mechanisms, an event observed in one of three BPDCN PDX studied. In summary, these results provide a preclinical proof-of-principle that allogeneic UCART123 cells have potent anti-BPDCN activity.

Date: 2022
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DOI: 10.1038/s41467-022-29669-8

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