Reference - Detail
| RRC ID | 53213 |
|---|---|
| Author | Nakazawa Y, Matsuda K, Kurata T, Sueki A, Tanaka M, Sakashita K, Imai C, Wilson MH, Koike K. |
| Title | Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34(+) cells of juvenile myelomonocytic leukemia. |
| Journal | J Hematol Oncol |
| 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. |
| Volume | 9 |
| Pages | 27 |
| Published | 2016-3-16 |
| DOI | 10.1186/s13045-016-0256-3 |
| PII | 10.1186/s13045-016-0256-3 |
| PMID | 26983639 |
| PMC | PMC4793548 |
| MeSH | Antigens, CD34 / genetics Antigens, CD34 / immunology* Cell Line, Tumor Cell Proliferation / drug effects Cells, Cultured Coculture Techniques Flow Cytometry Humans Immunotherapy, Adoptive K562 Cells Leukemia, Myelomonocytic, Juvenile / genetics Leukemia, Myelomonocytic, Juvenile / immunology* Leukemia, Myelomonocytic, Juvenile / therapy Ligands Mutation Receptors, Antigen, T-Cell / genetics Receptors, Antigen, T-Cell / immunology* Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / genetics Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / immunology* Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / immunology Stem Cell Factor / pharmacology T-Lymphocytes / immunology* T-Lymphocytes / metabolism T-Lymphocytes / transplantation Thrombopoietin / pharmacology |
| IF | 11.059 |
| Times Cited | 15 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 14 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Cord blood stem cells for research | |
| Human and Animal Cells | K562 |