Generation of immunostimulatory dendritic cells from the malignant clone in patients with juvenile myelomonocytic leukemia

Nabarro, Stephen; Thrasher, Adrian J.; Kempski, Helena; Amrolia, Persis; Anderson, John

doi:10.1038/sj.leu.2403059

Cited by 3 publications

(1 citation statement)

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“…There have been several reports of patients being successfully treated by donor lymphocyte infusions for post-transplant relapse [ 8 , 9 ], suggesting that immune-based therapies, such as T cell-mediated immunotherapy, may represent feasible treatment approaches in JMML. Nabarro et al [ 10 ] demonstrated the generation of immunostimulatory dendritic cells from malignant JMML clones. Allogenic T cells stimulated by leukemic dendritic cells were able to lyse leukemic JMML cells; however, this anti-leukemic effect may depend on alloimmune mechanisms and fail to direct activated T cells toward leukemia-associated antigens.…”

Section: Introductionmentioning

confidence: 99%

Anti-proliferative effects of T cells expressing a ligand-based chimeric antigen receptor against CD116 on CD34+ cells of juvenile myelomonocytic leukemia

et al. 2016

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BackgroundJuvenile 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.MethodsWe 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.ResultsGMR 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.ConclusionsLigand-based GMR CAR T cells may have anti-proliferative effects on stem and progenitor cells in JMML.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0256-3) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%