Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells

Mistry, Jayna J; Moore, Jamie A; Kumar, Prakrit R; Marlein, Christopher R.; Hellmich, Charlotte; Pillinger, Genevra; Jibril, Aisha; Palma, Federica Di; Collins, Angela; Bowles, Kristian M.; Rushworth, Stuart A.

doi:10.3324/haematol.2019.242974

Cited by 24 publications

(11 citation statements)

References 11 publications

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“…Acute myeloid leukemia (AML) is another disease where the anti-tumor effects of DARA have been investigated. In combination with all-trans retinoic acid (ATRA), DARA enhanced cytotoxicity of AML cells [ 70 ], while as a single agent, DARA induced an inhibition of mitochondrial transfer from mesenchymal stromal cells to AML cells, thus reducing the tumor burden [ 71 ]. Moreover, the efficacy of anti-CD38 therapy was assessed also in post-transplant refractory B-acute lymphoblastic leukemia [ 72 , 73 , 74 ].…”

Section: Clinical Applications Outside MMmentioning

confidence: 99%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

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Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

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Section: Clinical Applications Outside MMmentioning

confidence: 99%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

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“…A new study indicated that daratumumab, an anti-CD38 monoclonal antibody, could inhibit AML disease progression via a mechanism involving blocking mitochondrial transfer from MSCs to AML blasts. 176 As malignant tumors develop as part of a high-metabolic and invasive complex, future studies are required to investigate the profound effect of mitochondrial acquisition on the respiratory metabolism of cancer cells and to explore a valid approach for the inhibition of mitochondrial transfer in the TME with minimal side effects.…”

Section: Perspectives and Applicationsmentioning

confidence: 99%

Intercellular mitochondrial transfer as a means of tissue revitalization

Liu

Gao

Liu

et al. 2021

Sig Transduct Target Ther

193

152

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As the crucial powerhouse for cell metabolism and tissue survival, the mitochondrion frequently undergoes morphological or positional changes when responding to various stresses and energy demands. In addition to intracellular changes, mitochondria can also be transferred intercellularly. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, the intercellular mitochondrial transfer also occurs under physiological conditions. In this review, the phenomenon of mitochondrial transfer is described according to its function under both physiological and pathological conditions, including tissue homeostasis, damaged tissue repair, tumor progression, and immunoregulation. Then, the mechanisms that contribute to this process are summarized, such as the trigger factors and transfer routes. Furthermore, various perspectives are explored to better understand the mysteries of cell–cell mitochondrial trafficking. In addition, potential therapeutic strategies for mitochondria-targeted application to rescue tissue damage and degeneration, as well as the inhibition of tumor progression, are discussed.

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“…The surface molecule CD38 is critical for the transport of mitochondria from MSCs to AML cells [ 127 ]. Daratumumab, a monoclonal anti-CD38 antibody approved for the treatment of multiple myeloma, was shown to block the delivery of mitochondria to AML cells, decrease the oxygen consumption rate, and inhibit the growth of leukemic cells [ 128 , 129 ]. Main regulators of mitochondrial biogenesis and activity including PGC-1α and NOX2 are also promising targets.…”

Section: Combinatorial Strategies To Overcome Aml Resistance To Immunotherapymentioning

confidence: 99%

Catch me if you can: how AML and its niche escape immunotherapy

et al. 2021

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In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.

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Daratumumab inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells

Abstract: inhibits acute myeloid leukaemia metabolic capacity by blocking mitochondrial transfer from mesenchymal stromal cells.

Cited by 24 publications

References 11 publications

The Circular Life of Human CD38: From Basic Science to Clinics and Back

The Circular Life of Human CD38: From Basic Science to Clinics and Back

Intercellular mitochondrial transfer as a means of tissue revitalization

Catch me if you can: how AML and its niche escape immunotherapy

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