Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Viola, Domenico; Donà, Ada; Caserta, Enrico; Troadec, Estelle; Besi, Francesca; McDonald, Tinisha; Ghoda, Lucy; Gunes, Emine Gulsen; Sanchez, James F.; Khalife, Jihane; Martella, Marianna; Karanes, Chatchada; Htut, Myo; Wang, Xiuli; Rosenzweig, Michael; Chowdhury, Arnab; Sborov, Douglas W.; Miles, Rodney R.; Yazaki, Paul J.; Ebner, Todd; Hofmeister, Craig C.; Forman, Stephen J.; Rosen, Steven T.; Marcucci, Guido; Shively, John E.; Keats, Jonathan J.; Krishnan, Amrita; Pichiorri, Flavia

doi:10.1038/s41375-020-0810-4

Cited by 68 publications

(52 citation statements)

References 32 publications

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“…This demonstrates that in addition to inducing NK cell-mediated ADCC, isatuximab can also directly activate NK cells and enhance NK cell-killing capacity. Interestingly, Viola et al recently reported that daratumumab also directly activated NK cells (45). The authors further demonstrated that the daratumumab Fab fragment did not activate NK cells, indicating that without Fc receptor engagement, targeting CD38 alone cannot activate NK cells.…”

Section: Discussionmentioning

confidence: 94%

Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells

et al. 2020

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Section: Discussionmentioning

confidence: 94%

Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells

et al. 2020

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“…Contrarily, the normalization/increase in IFN-γ levels found after several cycles might be attributed to the engagement of this cytokine in daratumumab-mediated cytotoxicity against plasma cells. Additionally, daratumumab may exert its anti-plasma cells effect through the engagement of natural killer (NK) cells, as recently reported in MM ( 35 ).…”

Section: Discussionmentioning

confidence: 79%

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

et al. 2021

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Daratumumab is a monoclonal antibody directed against the transmembrane glycoprotein CD38 expressed on plasma cells and lymphoplasmocytes, with a proven efficacy in multiple myeloma. Here we show its clinical efficacy in a patient with cold agglutinin disease (CAD) relapsed after multiple lines of therapy. CAD is caused by cold reactive autoantibodies that induce complement mediated hemolysis and peripheral circulatory symptoms. The disease is also characterized by the presence of monoclonal IgM gammopathy and of a lymphoid bone marrow infiltration that benefits from B-cell targeting therapies (i.e., rituximab) but also from plasma cell directed therapies, such as proteasome inhibitors. In the patient described, we also show that daratumumab therapy influenced the dynamics of several immunoregulatory cytokine levels (IL-6, IL-10, IL-17, IFN-γ, TNF-α, TGF-β) indicating an immunomodulatory effect of the drug beyond plasma cell depletion. In addition, we provide a literature review on the use of daratumumab in autoimmune conditions, including multi-treated and refractory patients with autoimmune hemolytic anemia (both CAD and warm forms), Evans syndrome (association of autoimmune hemolytic anemia and immune thrombocytopenia) and non-hematologic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.

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“…3 Moreover, it has been proposed that anti-CD38 targeting induces the activation and degranulation of NK cell and leads to an increased expression of CD80/CD86 T cell costimulatory molecules on monocytes, which induces monocyte polarization and activation and stimulates T cell expansion via CD28 binding. 7…”

Section: Discussionmentioning

confidence: 99%

Relapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation

Yang

Jiang

Zhang

et al. 2021

Therapeutic Advances in Hematology

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Daratumumab is a humanized anti-CD38 IgG1 monoclonal antibody which could be used for multiple myeloma (MM). MM with plasma-cell leukemia (PCL) transformation is highly aggressive and is resistant to conventional therapy. Novel therapeutics are needed for PCL, and daratumumab may play role. We report a case of relapsed/refractory multiple myeloma (RRMM)-transformed PCL successfully treated with daratumumab. The case was a 42-year-old man who was diagnosed with MM 2 years ago and relapsed after six cycles of bortezomib-based chemotherapy. The patient rapidly developed hyperleukocytosis and disseminated intravascular coagulation, and was diagnosed with PCL. Daratumumab-based therapy was tried and the case miraculously obtained complete remission (CR) after four doses of a weekly infusion of daratumumab. Finally the patient received autologous hematopoietic stem-cell transplantation (auto-HSCT) and maintained CR. Moreover, we monitored the immune cell dynamics by flow cytometry (FCM) during daratumumab-based treatment. The immune cell subset analysis revealed significant down-regulation of CD38+ natural killer (NK) cells, regulatory T cells (Tregs) and regulatory B cells (Bregs). Meanwhile cytotoxic T-lymphocyte expansion was observed. In conclusion, daratumumab could rapidly decrease tumor burden, improve the condition of the PCL patient, and serve as a bridging salvage chemotherapy for further chimeric antigen recptor T cell therapy (Car-T) or HSCT, which could potentially improve patient survival. The immune cell dynamic findings in this case suggest that the immunomodulatory mechanism may contribute to the antimyeloma effect of daratumumab.

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Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Cited by 68 publications

References 32 publications

Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells

Isatuximab Acts Through Fc-Dependent, Independent, and Direct Pathways to Kill Multiple Myeloma Cells

The Immunomodulatory Effect and Clinical Efficacy of Daratumumab in a Patient With Cold Agglutinin Disease

Relapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation

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