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- Title
Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34<sup>+</sup> cells of juvenile myelomonocytic leukemia.
- Authors
Nakazawa, Yozo; Matsuda, Kazuyuki; Kurata, Takashi; Sueki, Akane; Tanaka, Miyuki; Sakashita, Kazuo; Imai, Chihaya; Wilson, Matthew H.; Koike, Kenichi
- Abstract
Background: Juvenile myelomonocytic leukemia (JMML) is a fatal, myelodysplastic/myeloproliferative neoplasm of early childhood. Patients with JMML have mutually exclusive genetic abnormalities in granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor (GMR, CD116) signaling pathway. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option for JMML; however, disease recurrence is a major cause of treatment failure. We investigated adoptive immunotherapy using GMR-targeted chimeric antigen receptor (CAR) for JMML. Methods: We constructed a novel CAR capable of binding to GMR via its ligand, GM-CSF, and generated piggyBac transposon-based GMR CAR-modified T cells from three healthy donors and two patients with JMML. We further evaluated the anti-proliferative potential of GMR CAR T cells on leukemic CD34+ cells from six patients with JMML (two NRAS mutations, three PTPN11 mutations, and one monosomy 7), and normal CD34+ cells. Results: GMR CAR T cells from healthy donors suppressed the cytokine-dependent growth of MO7e cells, but not the growth of K562 and Daudi cells. Co-culture of healthy GMR CAR T cells with CD34+ cells of five patients with JMML at effector to target ratios of 1:1 and 1:4 for 2 days significantly decreased total colony growth, regardless of genetic abnormality. Furthermore, GMR CAR T cells from a non-transplanted patient and a transplanted patient inhibited the proliferation of respective JMML CD34+ cells at onset to a degree comparable to healthy GMR CAR T cells. Seven-day co-culture of GMR CAR T cells resulted in a marked suppression of JMML CD34+ cell proliferation, particularly CD34+CD38- cell proliferation stimulated with stem cell factor and thrombopoietin on AGM-S3 cells. Meanwhile, GMR CAR T cells exerted no effects on normal CD34+ cell colony growth. Conclusions: Ligand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.
- Subjects
LEUKEMIA genetics; T cells; ANTIGEN receptors; CD34 antigen; GRANULOCYTE-macrophage colony stimulating factor receptors; TRANSPOSONS
- Publication
Journal of Hematology & Oncology, 2016, Vol 9, p1
- ISSN
1756-8722
- Publication type
Article
- DOI
10.1186/s13045-016-0256-3