Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1

Haruko Tashiro, Tim Sauer, Thomas Shum, Kathan Parikh, Maksim Mamonkin, Bilal Omer, Rayne H. Rouce, Premal Lulla, Cliona M. Rooney, Stephen Gottschalk, Malcolm Brenner

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

The successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment. C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by >80% of AML but is absent on normal HSCs. Here we describe the development and evaluation of CLL-1-specific chimeric antigen receptor T cells (CLL-1.CAR-Ts) and we demonstrate their specific activity against CLL-1+ AML cell lines as well as primary AML patient samples in vitro. CLL-1.CAR-Ts selectively reduced leukemic colony formation in primary AML patient peripheral blood mononuclear cells compared to control T cells. In a human xenograft mouse model, CLL-1.CAR-Ts mediated anti-leukemic activity against disseminated AML and significantly extended survival. By contrast, the colony formation of normal progenitor cells remained intact following CLL-1.CAR-T treatment. Although CLL-1.CAR-Ts are cytotoxic to mature normal myeloid cells, the selective sparing of normal hematopoietic progenitor cells should allow full myeloid recovery once CLL-1.CAR-T activity terminates. To enable elective ablation of the CAR-T, we therefore introduced the inducible caspase-9 suicide gene system and we show that exposure to the activating drug rapidly induced a controlled decrease of unwanted CLL-1.CAR-T activity against mature normal myeloid cells.

Original languageEnglish (US)
Pages (from-to)2202-2213
Number of pages12
JournalMolecular Therapy
Volume25
Issue number9
DOIs
StatePublished - Sep 6 2017

Keywords

  • AML
  • CAR
  • CLL-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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