Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia

Zhenhui, Wu; Zhang, Huan; Wu, Min; Peng, Guorui; He, Yanqiu; Wan, Na; Zeng, Ying-Jian

doi:10.1016/j.biopha.2021.111299

Cited by 21 publications

(15 citation statements)

References 126 publications

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“…In AML cells, the expression of the NKG2DLs, including MICA/B, ULBP1/2, and ULBP3 were found to be 0–75%, 16–63%, and 16–100%, respectively. In contrast, their expression levels on normal cells were found to be extremely low, making NKG2DLs ideal targets for AML [ 20 ]. However, immune escape of leukaemia stem cells (LSCs) is one of the fundamental causes of refractory/relapsed AML.…”

Section: Introductionmentioning

confidence: 99%

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

Pan

et al. 2022

Mol Cancer

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Background Patients with relapsed/refractory acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have limited treatment options and poor prognosis. Therefore, novel treatment modalities are needed. Since high expression of natural killer group 2 member D ligands (NKG2DLs) can be induced by FLT3 inhibitors, we constructed dual-target FLT3 single-chain fragment variable (scFv)/NKG2D-chimeric antigen receptor (CAR) T cells, and explored whether FLT3 inhibitors combined with FLT3scFv/NKG2D-CAR T cells could have synergistic anti-leukaemia effects. Methods FLT3scFv and NKG2D expression in CAR T cells, FLT3 and NKG2DL expression in AML cells, and the in vitro cytotoxicity of combining CAR T cells with gilteritinib were assessed by flow cytometry. The therapeutic effect was evaluated in a xenograft mouse model established by injection of MOLM-13 cells. Mechanisms underlying the gilteritinib-induced NKG2DL upregulation were investigated using siRNA, ChIP-QPCR and luciferase assays. Results The FLT3scFv/NKG2D-CAR T cells specifically lysed AML cells both in vitro and in the xenograft mouse model. The efficacy of FLT3scFv/NKG2D-CAR T cells was improved by gilteritinib-pretreatment. The noncanonical NF-κB2/Rel B signalling pathway was found to mediate gilteritinib-induced NKG2DL upregulation in AML cells. Conclusions Bispecific FLT3scFv/NKG2D-CAR T cells can effectively eradicate AML cells. The FLT3 inhibitor gilteritinib can synergistically improve this effect by upregulating NF-κB2-dependent NKG2DL expression in AML cells. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

Pan

et al. 2022

Mol Cancer

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“…Furthermore, patients who are candidates to CAR-T cell therapy have typically undergone multiple lines of treatment and intensive chemotherapy in prior interventions. In some instances, this intensive chemotherapy has been reported to induce DNA damage in AML cells resulting in the downregulation of target antigens ( Wu et al, 2021 ). Despite the limitations of CAR-T cell therapy in treating AML, there is a pressing need to develop new strategies to address the aforementioned limitations.…”

Section: Limitations Of Car-t Cell Therapy In Amlmentioning

confidence: 99%

Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations

Guijarro-Albaladejo,

Marrero-Cepeda,

Rodríguez-Arbolí

et al. 2024

Front. Cell Dev. Biol.

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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis despite the advent of novel therapies. Consequently, a major need exists for new therapeutic options, particularly for patients with relapsed/refractory (R/R) AML. In recent years, it has been possible to individualize the treatment of a subgroup of patients, particularly with the emergence of multiple targeted therapies. Nonetheless, a considerable number of patients remain without therapeutic options, and overall prognosis remains poor because of a high rate of disease relapse. In this sense, cellular therapies, especially chimeric antigen receptor (CAR)-T cell therapy, have dramatically shifted the therapeutic options for other hematologic malignancies, such as diffuse large B cell lymphoma and acute lymphoblastic leukemia. In contrast, effectively treating AML with CAR-based immunotherapy poses major biological and clinical challenges, most of them derived from the unmet need to identify target antigens with expression restricted to the AML blast without compromising the viability of the normal hematopoietic stem cell counterpart. Although those limitations have hampered CAR-T cell therapy translation to the clinic, there are several clinical trials where target antigens, such as CD123, CLL-1 or CD33 are being used to treat AML patients showing promising results. Moreover, there are continuing efforts to enhance the specificity and efficacy of CAR-T cell therapy in AML. These endeavors encompass the exploration of novel avenues, including the development of dual CAR-T cells and next-generation CAR-T cells, as well as the utilization of gene editing tools to mitigate off-tumor toxicities. In this review, we will summarize the ongoing clinical studies and the early clinical results reported with CAR-T cells in AML, as well as highlight CAR-T cell limitations and the most recent approaches to overcome these barriers. We will also discuss how and when CAR-T cells should be used in the context of AML.

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“…One of the best-studied activating receptors is NKG2D, a potent activating receptor which binds to MICA/B and ULBP-family molecules. NKG2D ligands are upregulated on a diversity of stressed and neoplastic cells through mechanisms involving oxidative stress, DNA damage, and inflammatory cytokine exposure ( 44 ). NKG2D can also be expressed on αβ and γδT cells, where it serves as a costimulatory molecule augmenting TCR signaling ( 45 ).…”

Section: Nk Cells In Amlmentioning

confidence: 99%

Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

Kent,

Crump,

Davila

2023

Front. Immunol.

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Acute myeloid leukemia (AML) remains an elusive disease to treat, let alone cure, even after highly intensive therapies such as stem cell transplants. Adoptive cell therapeutic strategies based on conventional alpha beta (αβ)T cells are an active area of research in myeloid neoplasms given their remarkable success in other hematologic malignancies, particularly B-cell-derived acute lymphoid leukemia, myeloma, and lymphomas. Several limitations have hindered clinical application of adoptive cell therapies in AML including lack of leukemia-specific antigens, on-target-off-leukemic toxicity, immunosuppressive microenvironments, and leukemic stem cell populations elusive to immune recognition and destruction. While there are promising T cell-based therapies including chimeric antigen receptor (CAR)-T designs under development, other cytotoxic lymphocyte cell subsets have unique phenotypes and capabilities that might be of additional benefit in AML treatment. Of particular interest are the natural killer (NK) and unconventional T cells known as invariant natural killer T (iNKT) and gamma delta (γδ) T cells. NK, iNKT, and γδT cells exhibit intrinsic anti-malignant properties, potential for alloreactivity, and human leukocyte-antigen (HLA)-independent function. Here we review the biology of each of these unconventional cytotoxic lymphocyte cell types and compare and contrast their strengths and limitations as the basis for adoptive cell therapies for AML.

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Targeting the NKG2D/NKG2D-L axis in acute myeloid leukemia

Cited by 21 publications

References 126 publications

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib

Chimeric antigen receptor (CAR) modified T Cells in acute myeloid leukemia: limitations and expectations

Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

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