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 KonoplevJun 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, Marina Konopleva

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Article number2228
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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