Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab

Kurdi, Ahmed T.; Glavey, Siobhán; Bezman, Natalie; Jhatakia, Amy; Guerriero, Jennifer L.; Manier, Salomon; Moschetta, Michele; Mishima, Yuji; Roccaro, Aldo M.; Detappe, Alexandre; Liu, Chia Jen; Sacco, Antonio; Huynh, Daisy; Tai, Yu Tzu; Robbins, Michael; Azzi, Jamil; Ghobrial, Irène M.

doi:10.1158/1535-7163.mct-17-0998

Cited by 77 publications

(68 citation statements)

References 50 publications

(57 reference statements)

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“…While monoclonal antibodies exert various mechanisms of targeting malignant cells in B-cell lymphoma, macrophage ADCP has been identified as a pre-dominant mechanism (18,28). In this light, previous reports examining ibrutinib in combination with rituximab that did not reveal synergy were mostly focused on NK-cell ADCC or relied on monocyte derived macrophages (20)(21)(22)(23)35).…”

Section: Discussionmentioning

confidence: 99%

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Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström´s Macroglobulinemia, Mantle cell lymphoma and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2 -/experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

“…As the antibody therapy relies on several independent effector mechanisms antibody-dependent cellular phagocytosis has been previously underestimated (28).…”

Section: Introductionmentioning

confidence: 99%

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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“…Since SLAMF7 is also expressed on NK cells, the cross-linking of SLAMF7 on NK cells by a treatment with elotuzumab induces NK cell activation via immunoreceptor tyrosine-based switch motifs (ITSM)-mediated signaling. These ITSM-mediated signaling enhances calcium signaling from ITAM-linked activating receptor, through an interaction between NKp46 and NKG2D and their ligands expressed on myeloma cells [142] or stimulates macrophage-mediated ADCP [143]. The phase III ELOQUENT-2 study (elotuzumab plus lenalidomide and dexamethasone vs lenalidomide and dexamethasone) reported a 29% reduction in risk of death or disease progression at 4 years in the elotuzumab arm of the trial [144] (Table S1).…”

Section: Inkt and Nk Cell-mediated Immunotherapymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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“…Importantly, EAT-2 is strongly expressed in NK cells, somewhat in γδ T cells, but not in B, CD4 + T, CD8 + T, or dendritic cells ( 62 , 75 ). Interestingly, CD16 + non-classical monocytes express both SLAMF7 and EAT-2 ( 39 , 76 ), indicating that SLAMF7 is likely signaling competent in this population of monocytes that is also capable of mediating antibody-dependent cellular phagocytosis (ADCP) through CD16 ( 77 ).…”

Section: Slamf7 Expression and Signaling In Leukocytes (Summarized Inmentioning

confidence: 99%

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

2018

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Multiple myeloma (MM) is a bone marrow plasma cell neoplasm and is the second most-common hematologic malignancy. Despite advances in therapy, MM remains largely incurable. Elotuzumab is a humanized IgG1 monoclonal antibody targeting SLAMF7, which is highly expressed on myeloma cells, and the antibody is approved for the treatment of relapsed and/or refractory (RR) MM in combination with lenalidomide and dexamethasone. Elotuzumab can stimulate robust antibody-dependent cellular cytotoxicity (ADCC) through engaging with FcγRIIIA (CD16) on NK cells and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Interestingly, SLAMF7 is also expressed on cytolytic NK cells, which also express the requisite adaptor protein, EAT-2, to mediate activation signaling. Accumulating evidence indicates that antibody crosslinking of SLAMF7 on human and mouse NK cells can stimulate EAT-2-dependent activation of PLCγ, ERK, and intracellular calcium mobilization. The binding of SLAMF7 by elotuzumab can directly induce signal transduction in human NK cells, including co-stimulation of the calcium signaling triggered through other surface receptors, such as NKp46 and NKG2D. In RRMM patients, elotuzumab monotherapy did not produce objective responses, but did enhance the activity of approved standard of care therapies, including lenalidomide or bortezomib, which are known to enhance anti-tumor responses by NK cells. Taken together, these preclinical results and accumulating experience in the clinic provide compelling evidence that the mechanism of action of elotuzumab in MM patients involves the activation of NK cells through both CD16-mediated ADCC and direct co-stimulation via engagement with SLAMF7, as well as promoting ADCP by macrophages. We review the current understanding of how elotuzumab utilizes multiple mechanisms to facilitate immune-mediated attack of myeloma cells, as well as outline goals for future research.

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Antibody-Dependent Cellular Phagocytosis by Macrophages is a Novel Mechanism of Action of Elotuzumab

Cited by 77 publications

References 50 publications

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Mechanisms of NK Cell Activation and Clinical Activity of the Therapeutic SLAMF7 Antibody, Elotuzumab in Multiple Myeloma

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