Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

Saltarella, Ilaria; Desantis, Vanessa; Melaccio, Assunta; Solimando, Antonio Giovanni; Lamanuzzi, Aurelia; Ria, Roberto; Storlazzi, Clelia Tiziana; Mariggiò, Maria Addolorata; Vacca, Angelo; Frassanito, Maria Antonia

doi:10.3390/cells9010167

Cited by 89 publications

(97 citation statements)

References 84 publications

(137 reference statements)

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“…However, the predicted efficacy of these mAbs is largely dependent on the mechanisms of resistance to anti-CD38 mAbs. Resistance to ADCC (e.g., fratricidal depletion of CD38+ NK cells), CDC (e.g., upregulation of complement-inhibitory molecules) and ADCP (e.g., upregulation of CD47 inhibiting phagocytosis) have been observed during anti-CD38 mAb treatment and strategies to overcome them are under clinical investigation [96]. Nevertheless, the most relevant issue limiting retreatment with anti-CD38 mAbs is the long-lasting downregulation of CD38 on plasma cell surfaces after anti-CD38 therapy [97].…”

Section: Future Directions and Conclusionmentioning

confidence: 99%

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

D’Agostino

Innorcia

Boccadoro

et al. 2020

IJMS

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Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs.

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Section: Future Directions and Conclusionmentioning

confidence: 99%

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

D’Agostino

Innorcia

Boccadoro

et al. 2020

IJMS

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“…Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells (PCs) accumulating and disseminating in the bone marrow (BM) with ensuing induction of focal skeletal lesions and osteoporosis driving myeloma bone disease, anemia, renal insufficiency, hypercalcemia [ 72 ], higher infection rates [ 73 , 74 , 75 ], and secondary life-threatening complications [ 76 , 77 , 78 ]. MM represents an ideal model of colonization and interaction of tumor cells in the bone microenvironment [ 79 , 80 , 81 ], where the immune-milieu [ 82 , 83 ] and aberrant angiogenesis shape a permissive ecosystem, supporting disease progression via a plethora of autocrine [ 84 , 85 ] and paracrine loops [ 86 , 87 ].…”

Section: Multiple Myeloma (Mm) As a Paradigm For Endothelial Gatekmentioning

confidence: 99%

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

Solimando

Summa

Vacca

et al. 2020

Cancers

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Cancer-associated neo vessels’ formation acts as a gatekeeper that orchestrates the entrance and egress of patrolling immune cells within the tumor milieu. This is achieved, in part, via the directed chemokines’ expression and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. The crosstalk between adaptive immune cells and the cancer endothelium is thus essential for tumor immune surveillance and the success of immune-based therapies that harness immune cells to kill tumor cells. This review will focus on the biology of the endothelium and will explore the vascular-specific molecular mediators that control the recruitment, retention, and trafficking of immune cells that are essential for effective antitumor immunity. The literature revision will also explore how abnormalities in the tumor endothelium impair crosstalk with adaptive immune cells and how targeting these abnormalities can improve the success of immune-based therapies for different malignancies, with a particular focus on the paradigmatic example represented by multiple myeloma. We also generated and provide two original bio-informatic analyses, in order to sketch the physiopathology underlying the endothelial–neoplastic interactions in an easier manner, feeding into a vicious cycle propagating disease progression and highlighting novel pathways that might be exploited therapeutically.

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“…Anti-CD38 antibodies can bind the Fc gamma receptors (FcgRs) (44) on the immune effector cells inducing the ADCC (40). The binding with the Fc fragment of the anti-CD38 mAbs produces the intracellular phosphorylation of the tyrosine-based activating motifs of the FcgRs that leads in the lysis of MM cells (45). In particular the cell types FcgRs-expressing that are mainly involved in the ADCC-anti-CD38 mAbs mediated are NK cells which express CD32 and CD16, monocytes expressing CD16 and macrophages CD64 + (45).…”

Section: Antibody-dependent Cell-mediated Cytotoxicity (Adcc)mentioning

confidence: 99%

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

et al. 2021

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Monoclonal antibodies (mAbs) directed against antigen-specific of multiple myeloma (MM) cells have Fc-dependent immune effector mechanisms, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), but the choice of the antigen is crucial for the development of effective immuno-therapy in MM. Recently new immunotherapeutic options in MM patients have been developed against different myeloma-related antigens as drug conjugate-antibody, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)-T cells. In this review, we will highlight the mechanism of action of immuno-therapy currently available in clinical practice to target CD38, SLAMF7, and BCMA, focusing on the biological role of the targets and on mechanisms of actions of the different immunotherapeutic approaches underlying their advantages and disadvantages with critical review of the literature data.

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Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

Cited by 89 publications

References 84 publications

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

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