Journal
MOLECULAR THERAPY
Volume 25, Issue 9, Pages 2202-2213Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.05.024
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Funding
- National Cancer Institute (NCI) [P01CA094237]
- National Cancer Institute (NCI) (NCI Cancer Center) [P30CA125123]
- Leukemia Lymphoma Society [6483-16]
- Cancer Prevention Research Institute of Texas (CPRIT) [RP160693]
- NIH/NHBLI [T32HL092332]
- NIH/NIDDK [T32DK060445]
- Howard Hughes Medical Institute Med into Grad Initiative
- Leukemia Texas grant
- American Society for Blood and Marrow Transplantation (ASBMT)
- Grants-in-Aid for Scientific Research [16K14634] Funding Source: KAKEN
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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.
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