Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation

Basak, Grzegorz; Wreede, Liesbeth C. de; Biezen, Anja van; Wiktor-Jedrzejczak, W; Hałaburda, Kazimierz; Schmid, Christoph; Dazzi, Francesco; Borne, Peter A. von dem; Petersen, Eefke; Beelen, Dietrich W.; Abayomi, Akin; Volin, Liisa; Buzyn, Agnès; Gürman, Günhan; Bunjes, Donald; Guglielmi, Cesare; Olavarría, Eduardo; Witte, Théo de

doi:10.1038/bmt.2012.234

Cited by 10 publications

(6 citation statements)

References 20 publications

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“…With the success of TKI treatments, TKIs clearly remain the best, safest, and easiest-to-manage first-line therapy for CML in the clinical setting, though they do not eradiate residual CML stem cells and do not biologically cure the disease, though most patients with CML are considered clinically cured. CML disease is highly susceptible to the allogenic immune system, as indicated by allo-SCT (42) and DLI (43), making advanced phases of CML, high-risk disease, or disease in the chronic phase that is resistant or intolerant to TKIs the ideal candidate for allogenic donor-derived CAR T-cell immunotherapy (DLI administration). In this context, matched human leukocyte antigen donor T cells may be used as a source of GMTCs in sequential association with TKIs or allo-SCT.…”

Section: Discussionmentioning

confidence: 99%

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells

et al. 2019

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Chronic myeloid leukemia (CML) is a chronic disease resulting in myeloid cell expansion through expression of the BCR-ABL1 fusion transcript. Tyrosine kinase inhibitors (TKI) have significantly increased survival of patients with CML, and deep responders may consider stopping the treatment. However, more than 50% of patients relapse and restart TKI, subsequently suffering unknown toxicity. Because CML is a model immune system-sensitive disease, we hypothesize that chimeric antigen receptor (CAR) T cells targeting IL1 receptor-associated protein (IL1RAP) in quiescent CML stem cells may offer an opportunity for a permanent cure. In this study, we produced and molecularly characterized a specific monoclonal anti-IL1RAP antibody from which fragment antigen-binding nucleotide coding sequences were cloned as a single chain into a lentiviral backbone and secured with the suicide gene iCASP9/rimiducid system. Our CAR T-cell therapy exhibited cytotoxicity against both leukemic stem cells and, to a lesser extent, monocytes expressing IL1RAP, with no apparent effect on the hematopoietic system, including CD34 þ stem cells. This suggests IL1RAP as a tumor-associated antigen for immunotherapy cell targeting. IL1RAP CAR T cells were activated in the presence of IL1RAP þ cell lines or primary CML cells, resulting in secretion of proinflammatory cytokines and specifically killing in vitro and in a xenograft murine model. Overall, we demonstrate the proof of concept of a CAR T-cell immunotherapy approach in the context of CML that is applicable for young patients and primary TKI-resistant, intolerant, or allograft candidate patients. Significance: These findings present the first characterization and proof of concept of a chimeric antigen receptor directed against IL1RAP expressed by leukemic stem cells in the context of CML.

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Section: Discussionmentioning

confidence: 99%

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells

et al. 2019

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“…When the disease burden at relapse was not taken into consideration, there was no significant difference in outcomes between the treatment groups, and the results were comparable to previously published reports of DLI or TKI treatment. 10,21,22 However, patients with aggressive relapses are less likely to receive DLI because of the difficulty of administering the donor product in a timely manner, especially in an unrelated-donor HCT setting. Moreover, patients with severe GVHD or significant comorbidities are less likely to receive DLI.…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Long-Term Outcomes of Donor Lymphocyte Infusions and Tyrosine Kinase Inhibitors in Patients With Relapsed CML After Allogeneic Hematopoietic Cell Transplantation

Shanavas

Messner

Kamel‐Reid

et al. 2014

Clinical Lymphoma Myeloma and Leukemia

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“…Various sources of hematopoietic progenitor cells (HPCs) are available for hematopoietic stem cell transplantation (HSCT), including bone marrow (BM), umbilical cord blood (CB), and peripheral blood (PB), in some cases mobilized with granulocyte colony-stimulating factor (G-CSF) (G-PB) [1][2][3]. The absolute number and intrinsic biological properties of HPCs differ among these 3 sources, affecting the speed of hematopoietic recovery after HSCT.…”

Section: Introductionmentioning

confidence: 99%

Gene and miRNA Expression Profiles of Hematopoietic Progenitor Cells Vary Depending on Their Origin

Báez

Martín-Antonio²,

Piruat

et al. 2014

Biology of Blood and Marrow Transplantation

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Hematopoietic progenitor cells (HPCs) from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood (G-PB), bone marrow (BM), or umbilical cord blood (CB) have differing biological properties and differing kinetics of engraftment post-transplantation, which might be explained, at least in part, by differing gene and miRNA expression patterns. To assess the differences in gene and miRNA expression, we analyzed whole genome expression profiles as well as the expression of 384 miRNAs in CD34(+) cells isolated from 18 healthy individuals (6 individuals per subtype of HPC source). We identified 43 genes and 36 miRNAs differentially expressed in the various CD34(+) cell sources. We observed that CD34(+) cells from CB and BM showed similar gene and miRNA expression profiles, whereas CD34(+) cells from G-PB had a very different expression pattern. Remarkably, 20 of the differentially expressed genes are targets of the differentially expressed miRNAs. Of note, the majority of genes differentially expressed in CD34(+) cells from G-PB are involved in cell cycle regulation, promoting the process of proliferation, survival, hematopoiesis, and cell signaling, and are targets of overexpressed and underexpressed miRNAs in CD34(+) cells from the same source. These data suggest significant differences in gene and miRNA expression among the various HPC sources used in transplantation. We hypothesize that the differentially expressed genes and miRNAs involved in cell cycle and proliferation might explain the differing kinetics of engraftment observed after transplantation of hematopoietic stem cells obtained from these different sources.

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Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation

Cited by 10 publications

References 20 publications

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells

CML Hematopoietic Stem Cells Expressing IL1RAP Can Be Targeted by Chimeric Antigen Receptor–Engineered T Cells

A Comparison of Long-Term Outcomes of Donor Lymphocyte Infusions and Tyrosine Kinase Inhibitors in Patients With Relapsed CML After Allogeneic Hematopoietic Cell Transplantation

Gene and miRNA Expression Profiles of Hematopoietic Progenitor Cells Vary Depending on Their Origin

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