In vivo vaccination effect in multiple myeloma patients treated with the monoclonal antibody isatuximab

Atanackovic, Djordje; Yousef, Sara; Shorter, Christa; Tantravahi, Srinivas K.; Steinbach, Mary; Iglesias, Fiorella; Sborov, Douglas W.; Radhakrishnan, Sabarinath Venniyil; Chiron, Marielle; Miles, Rodney R.; Salama, Mohamed E.; Luetkens, Tim

doi:10.1038/s41375-019-0536-3

Cited by 33 publications

(37 citation statements)

References 12 publications

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“…Although the role of NK cells in Dara mechanisms of action have been highly debated, here we show that the therapeutic targeting of CD38+NK cells may play a pivotal role in initiating a Th1 immune response, 30,31 which can be an essential component in mounting a powerful anti-CD38 immune response, as recently reported by Atanackovic et al 32 In agreement with Wang et al, 17 we demonstrate that Dara induces NK cell degranulation and IFN-γ release, but we show that this effect is restricted to Dara binding to the CD38+ NK cell population, which is indicated to be the only one expressing CD16 on their surface. We additionally observed a considerable increase in CD69 activation marker and GM-CSF production and an increase in Ca 2+ mobilization in NK cells treated with Dara, which suggests that Dara induces a substantial NK cell activation, a possible explanation as to why we and others observe a significant drop in NK cell frequency in Dara-treated patients.…”

Section: Discussionsupporting

confidence: 79%

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

Viola¹,

Donà²,

Caserta³

et al. 2019

Preprint

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AbstractDaratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Dara’s immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

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Section: Discussionsupporting

confidence: 79%

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

Viola¹,

Donà²,

Caserta³

et al. 2019

Preprint

Self Cite

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“…Both antibody-positive patients had also developed polyclonal T-cell responses against CD38. Importantly, the authors did not observe any new or increasing autologous antibody responses against MM-associated antigens in the two other patients who had not clinically responded to isatuximab, indicating that antigen-specific immune responses may be used as biomarkers to predict response to anti-CD38 therapies [93].…”

Section: Predictive Biomarkers For Cd38 Antibodiesmentioning

confidence: 94%

“…Atanackovic and colleagues [93] performed immunophenotyping of four patients with MM being treated with isatuximab enrolled in a phase 1 clinical study (NCT02514668). They found that two patients who had little to no preexisting antibody responses at baseline did not develop any new antibody responses during isatuximab treatment.…”

Section: Predictive Biomarkers For Cd38 Antibodiesmentioning

confidence: 99%

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

Martin

Corzo

Chiron

et al. 2019

Cells

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124

151

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CD38 is a transmembrane glycoprotein with ectoenzymatic activity involved in regulation of migration, signal transduction, and receptor-mediated adhesion. CD38 is highly expressed on various malignant cells, including multiple myeloma (MM), and at relatively low levels in other tissues, making it a suitable target for therapeutic antibodies. Several anti-CD38 therapies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab (SAR650984), respectively. Studies have shown that anti-CD38 therapies are effective in the treatment of relapsed/refractory MM and are well tolerated, with infusion reactions being the most common side effects. They can be used as monotherapy or in combination with immunomodulatory agents, such as pomalidomide, or proteasome inhibitors to potentiate their activity. Here we examine isatuximab and several anti-CD38 agents in development that were generated using new antibody engineering techniques and that may lead to more effective CD38 targeting. We also summarize trials assessing these antibodies in MM, other malignancies, and solid organ transplantation. Finally, we propose that further research on the mechanisms of resistance to anti-CD38 therapy and the development of biomarkers and new backbone regimens with CD38 antibodies will be important steps in building more personalized treatment for patients with MM.

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“…The loss of CD22 may be of clinical utility in CD22 CAR-T therapy. Moreover, improvements in CD22-based therapy may derive from implementation of biotechnological constructs enabling therapeutic antibodies to bind single or multiple molecules, leading to new ways of providing lytic effects [53].…”

Section: Discussionmentioning

confidence: 99%

CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

Lanza

Madon

Rondoni

et al. 2020

Cancers

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CD22 is a surface molecule expressed early during the ontogeny of B cells in the bone marrow and spleen, and can be found on B cells isolated from the different lymphoid compartments in humans. CD22 is expressed by most blasts from the majority (60–90%) of B-cell acute lymphoblastic leukemia (B-ALL). Current therapies in adults with newly diagnosed B-ALL are associated with complete remission (CR) rates of 50–90%. However, 30–60% of these patients relapse, and only 25–40% achieve disease-free survival of three years or more. Chemotherapy regimens for patients with refractory/relapsed B-ALL are associated with CR rates ranging from 31% to 44%. Novel immune-targeted therapies, such as blinatumomab and inotuzumab (a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin), provide potential means of circumventing chemo-refractory B-ALL cells through novel mechanisms of action. Eighty percent of inotuzumab-treated B-ALL patients may achieve a CR state. This review is focused on the biological and clinical activities of CD22 antibodies in B-ALL, and provides evidence about the potential role played by qualitative and quantitative analysis of the CD22 molecule on individual B-ALL blasts in predicting the depletion of leukemic cells, and, ultimately, leading to better clinical response rates.

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In vivo vaccination effect in multiple myeloma patients treated with the monoclonal antibody isatuximab

Cited by 33 publications

References 12 publications

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

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

Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab

CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

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