Journal
CLINICAL CANCER RESEARCH
Volume 24, Issue 2, Pages 370-382Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-2228
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Funding
- Leukemia and Lymphoma Society Translational Research Program [6265-13]
- Canadian Cancer Society Research Institute [704121]
- Canadian Institutes of Health Research Proof of Principle Grant [141723]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL002345, ZIAHL006090] Funding Source: NIH RePORTER
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Purpose: To explore the potential of ex vivo expanded healthy donor-derived allogeneic CD4 and CD8 double-negative cells (DNT) as a novel cellular immunotherapy for leukemia patients. Experimental Design: Clinical-grade DNTs from peripheral blood of healthy donors were expanded and their antileukemic activity and safety were examined using flow cytometry-based in vitro killing assays and xenograft models against AML patient blasts and healthy donor-derived hematopoietic cells. Mechanism of action was investigated using antibody-mediated blocking assays and recombinant protein treatment assays. Results: Expanded DNTs from healthy donors target a majority (36/46) of primary AML cells, including 9 chemotherapy-resistant patient samples in vitro, and significantly reduce the leukemia load in patient-derived xenograft models in a DNT donor-unrestricted manner. Importantly, allogeneic DNTs do not attack normal hematopoietic cells or affect hematopoietic stem/progenitor cell engraftment and differentiation, or cause xenogeneic GVHD in recipients. Mechanistically, DNTs express high levels of NKG2D and DNAM-1 that bind to cognate ligands preferentially expressed on AML cells. Upon recognition of AML cells, DNTs rapidly release IFN gamma, which further increases NKG2D and DNAM-1 ligands' expression on AML cells. IFN gamma pretreatment enhances the susceptibility of AML cells to DNT-mediated cytotoxicity, including primary AML samples that are otherwise resistant to DNTs, and the effect of IFN gamma treatment is abrogated by NKG2D and DNAM1-blocking antibodies. Conclusions: This study supports healthy donor-derived allogeneic DNTs as a therapy to treat patients with chemotherapy resistant AML and also reveals interrelated roles of NKG2D, DNAM-1, and IFN gamma in selective targeting of AML by DNTs. (C) 2017 AACR.
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