FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2936942313> ?p ?o ?g. }

• W2936942313 endingPage "418" @default.
• W2936942313 startingPage "416" @default.
• W2936942313 abstract "CD38-targeted therapy is emerging as one of the most effective immunotherapies ever developed for the treatment of multiple myeloma (MM) 1. CD38 is a transmembrane glycoprotein that serves as a receptor with a multifunctional ecto-enzymatic activity, which is highly expressed on plasma-cells, but also on several other cells belonging to the hemopoietic as well as to the non-hemopoietic tissues 2. Daratumumab, a fully human IgG1-kappa monoclonal antibody, is the first-in-class antibody targeting CD38. It has rapidly become a cornerstone of the anti-MM treatment, showing activity both as single agent in heavily pretreated MM patients and in combination with other agents. To date, daratumumab has been approved for newly diagnosed MM patients not eligible for autologous transplant in combination with bortezomib-melphalan-prednisone (D-VMP), and for relapsed/refractory (RR)MM patients as monotherapy or in combination with lenalidomide-dexamethasone (D-Rd), bortezomib-dexamethasone (D-Vd) (in the European Union), and pomalidomide-dexamethasone (D-Pd) (in the United States). Despite the great efficacy displayed by daratumumab, all responding patients ultimately acquire resistance to the drug and progress while on therapy; a better knowledge of its mechanisms of action and of the various mechanisms of resistance is essential for optimal development and use of these treatment options. CD38-targeted therapy represents a unique opportunity to concurrently impact on tumor cells and tumor microenvironment 2 because CD38 is expressed on myeloma cells, immune effector cells (natural killer [NK] cells, cytotoxic T cells, B cells, Vγ9Vδ2 T cells), and inhibitory cells, such as regulatory T cells (Tregs), regulatory B cells (Bregs), and myeloid-derived suppressor cells (MDSCs). Daratumumab exploits classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and apoptosis upon secondary cross-linking, which are dependent on CD38 expression on the tumor cells 3. Because CD38 is expressed on various immune cell populations, the potential immunomodulatory effects of daratumumab monotherapy in RRMM patients have recently been investigated, showing a multifaceted immunomodulatory role for daratumumab through the eradication of CD38-positive immune suppressor cells (e.g., Tregs, Bregs, and MDSCs) 4. The disappearance of an immunosuppressive contexture results in CD4+ and CD8+ T cell expansion, alloreactive functional T-cell responses, increased T-cell clonality, and in a potentially better host's anti-tumor immune response. Moreover, it has been shown that daratumumab may also reduce adenosine production in the bone marrow microenvironment through the modulation of CD38 enzymatic activity both on tumor cells and on cytotoxic T cells, thus promoting their antitumor activity 5. The immunomodulatory functions of daratumumab contributed to elucidate the significant clinical benefits and enhanced survival observed. However, given the expected increasing use of daratumumab in early lines of therapy, a deeper and extensive analysis of its effects on frequency and functional role of additional immune cell populations is urgently needed to identify possible resistance mechanisms. All the available reports about the impact of daratumumab treatment on immune CD38+ cells were based on the use of flow cytometry tools, which strongly limited the number of immune cell subpopulations that could be investigated at once. In the paper recently published in “Cytometry Part A” 6, Adams et al. reported how they extended and complemented their previous findings 4, 7, 8 using the Cytometry by Time of Flight (CyTOF®), a novel platform for high-dimensional phenotypic and functional analysis of single cells. CyTOF® is a next-generation flow cytometry platform with several technological advances, as compared to the conventional fluorescence-based flow cytometry 9, 10. The CyTOF® system does not depend on the detection of fluorescence, which requires compensation for spillover into adjacent channels, but on the use of elemental metal isotopes conjugated to monoclonal antibodies, thus identifying discrete isotope peaks without substantial overlap. Moreover, the platform allows for the detection of 42+ unique parameters rather than the 8–12 parameters included in a standard flow cytometry panel, and it can be customized for the analysis of both phenotypic and functional markers. By taking advantage of the resolution, sensitivity and dynamic range of mass spectrometry on a time-scale that allows the measurement of 1,000 individual cells per second, this configuration offers a new and valuable approach to high-content cytometric analysis. Adams et al. identified new modifications in immune cell profile that correlated with the efficacy and depth of response observed during treatment with daratumumab in RRMM patients. As already demonstrated by their previous flow cytometric analyses, they pointed out a decreased expression of CD38 on several immune cells (plasma cells, NK cells, monocytes, B cells, and T cells) in daratumumab-treated patients. Although NK cells disappeared after daratumumab treatment, the remaining NK cells displayed an activated phenotype both in peripheral blood and in bone marrow, increasing CD69, CD127, CD25, CD27, and CD137 expression and decreasing CD45RA and granzyme B expression. These new observations corroborated their earlier findings 8 according to which, although NK cells were reduced after daratumumab treatment, they were not completely depleted and could still contribute to ADCC, clinical efficacy, and infections control. Recently, Wang and colleagues 11 discovered a fratricide mechanism for daratumumab-mediated NK-cell depletion and provided a potential therapeutic strategy to overcome this side effect in daratumumab-treated MM patients. It would be fascinating to pursue—through the analysis of combinatorial expression of multiple phenotypic markers with the CyTOF® platform—the influence of daratumumab treatment on diverse functional properties of NK cells, thus discerning between immunoregulatory NK cells (CD56bright/CD16dim/neg) and cytotoxic NK cells (CD56dim/CD16bright). Daratumumab treatment could affect the immunoregulatory NK-cell subset reducing its number but could also promote the cytotoxic NK-cell compartment by increasing its CD107a and CD69 expression and IFNγ secretion. Accordingly, the best attractive partners to combine with daratumumab are immunomodulatory drugs (IMiDs) because they are able to enhance or prolong the functionality of cytotoxic NK cells. Moreover, Adams et al. observed a reduced percentage of CD38+ basophils and a shift toward an increased killing ability of the cytotoxic T cells after daratumumab monotherapy treatment, thus further confirming the previously reported daratumumab-mediated depletion of immune-suppressive populations. These results highlighted the importance of CyTOF® and related methodologies in obtaining a deeper understanding of the mechanism of action of daratumumab as monotherapy and in combination with other agents. At once, the CyTOF® platform could be very useful to identify cellular mediators of resistance to anti-CD38 therapy and to define potential mechanisms to restore sensitivity to daratumumab. Several factors contributing to the development of resistance to the immunomodulatory activities of daratumumab in MM patients have been already elucidated, such as the expression levels of complement inhibitory proteins CD55 and CD59 on MM cells 7 and immunogenetic factors involved in the effector cell function (e.g., the Fcγ receptor polymorphisms) 12. The compensatory upregulation of multiple inhibitory immune checkpoints (ICP/ICP-L) can also promote the resistance to the immunomodulatory activities of CD38 antibodies. The concurrent expression of a wide array of ICP/ICP-L and CD38 on the same cells in the tumor microenvironment strongly suggests a cross-talk between these molecules and their downstream signaling pathways. Interestingly, the existence of such a cross-talk has recently been reported in NSCLC and melanoma mouse models 13. Preclinical results suggested that CD38 upregulation on tumor cells could represent an escape mechanism from the infiltrating cytotoxic T cells induced by anti-PD-L1/PD-1 therapy. The combination of anti-CD38 and anti-PD-L1 proved to be more effective than either monotherapy alone in suppressing primary tumor growth and metastases in these tumor models. Studies in syngeneic mouse models (colon adenocarcinoma, plasmacytoma, and lung carcinoma) and in vitro assays confirmed that the combination of anti-CD38 and anti-PD-1 treatments can be more effective than targeting either pathway alone. These preclinical premises suggested the development of clinical trials evaluating whether the anti-MM activity of CD38 antibodies could be enhanced with PD-1 or PD-L1 inhibitors. Moreover, the upregulation of inhibitory receptors (PD-1, TIM-3, LAG-3, TIGIT) on effector cells could also involve daratumumab-resistant patients, because they are markers associated with a functional exhausted phenotype. Some preliminary observations derived from the recent study by Adams et al. revealed that the percentage of PD1+ CD8+ T cells decreased from baseline in daratumumab-responder patients but increased in non-responders, suggesting that the checkpoint receptor expression profile on effector cells could influence the clinical efficacy of daratumumab treatment and/or represent a remarkable mechanism of resistance. A systematic investigation of the peripheral blood and bone marrow “immunome” (immune cell profile) of daratumumab-treated MM patients could reveal an expansion of exhausted T cells with upregulation of the checkpoint inhibitors in resistant patients, suggesting the exploration of ICP-blocking strategies (anti-TIM3, anti-LAG-3, anti-TIGIT) as potential approaches to restore sensitivity to daratumumab. A more effective use of daratumumab in the treatment of MM patients will likely depend on a deeper knowledge of the significant changes in the immune system and of the tumor-related features derived from daratumumab exposure, including its modulation of the immune system and the tumor-acquired mechanisms of resistance. No funding was provided for this contribution. RM has received honoraria from Amgen, Celgene, and Janssen. FG has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda; has served on the advisory boards for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Roche, and Takeda. BC declares no competing financial interests." @default.
• W2936942313 created "2019-04-25" @default.
• W2936942313 creator A5004911570 @default.
• W2936942313 creator A5008807112 @default.
• W2936942313 date "2019-03-25" @default.
• W2936942313 modified "2023-09-24" @default.
• W2936942313 title "CyTOF®: A New Tool to Decipher the Immunomodulatory Activity of Daratumumab" @default.
• W2936942313 cites W1902692042 @default.
• W2936942313 cites W1938402249 @default.
• W2936942313 cites W2024626836 @default.
• W2936942313 cites W2346039638 @default.
• W2936942313 cites W2400276917 @default.
• W2936942313 cites W2439803058 @default.
• W2936942313 cites W2765695907 @default.
• W2936942313 cites W2767256995 @default.
• W2936942313 cites W2793410559 @default.
• W2936942313 cites W2799762478 @default.
• W2936942313 cites W2884332748 @default.
• W2936942313 cites W2891882983 @default.
• W2936942313 cites W2905082484 @default.
• W2936942313 doi "https://doi.org/10.1002/cyto.a.23752" @default.
• W2936942313 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30908843" @default.
• W2936942313 hasPublicationYear "2019" @default.
• W2936942313 type Work @default.
• W2936942313 sameAs 2936942313 @default.
• W2936942313 citedByCount "4" @default.
• W2936942313 countsByYear W29369423132020 @default.
• W2936942313 countsByYear W29369423132021 @default.
• W2936942313 countsByYear W29369423132022 @default.
• W2936942313 countsByYear W29369423132023 @default.
• W2936942313 crossrefType "journal-article" @default.
• W2936942313 hasAuthorship W2936942313A5004911570 @default.
• W2936942313 hasAuthorship W2936942313A5008807112 @default.
• W2936942313 hasBestOaLocation W29369423131 @default.
• W2936942313 hasConcept C164614171 @default.
• W2936942313 hasConcept C203014093 @default.
• W2936942313 hasConcept C2776063141 @default.
• W2936942313 hasConcept C2776364478 @default.
• W2936942313 hasConcept C2781119759 @default.
• W2936942313 hasConcept C60644358 @default.
• W2936942313 hasConcept C70721500 @default.
• W2936942313 hasConcept C86803240 @default.
• W2936942313 hasConceptScore W2936942313C164614171 @default.
• W2936942313 hasConceptScore W2936942313C203014093 @default.
• W2936942313 hasConceptScore W2936942313C2776063141 @default.
• W2936942313 hasConceptScore W2936942313C2776364478 @default.
• W2936942313 hasConceptScore W2936942313C2781119759 @default.
• W2936942313 hasConceptScore W2936942313C60644358 @default.
• W2936942313 hasConceptScore W2936942313C70721500 @default.
• W2936942313 hasConceptScore W2936942313C86803240 @default.
• W2936942313 hasIssue "4" @default.
• W2936942313 hasLocation W29369423131 @default.
• W2936942313 hasLocation W29369423132 @default.
• W2936942313 hasLocation W29369423133 @default.
• W2936942313 hasOpenAccess W2936942313 @default.
• W2936942313 hasPrimaryLocation W29369423131 @default.
• W2936942313 hasRelatedWork W1576282658 @default.
• W2936942313 hasRelatedWork W1991616922 @default.
• W2936942313 hasRelatedWork W2009358682 @default.
• W2936942313 hasRelatedWork W2046783221 @default.
• W2936942313 hasRelatedWork W2052897160 @default.
• W2936942313 hasRelatedWork W2102142132 @default.
• W2936942313 hasRelatedWork W2164975333 @default.
• W2936942313 hasRelatedWork W2936942313 @default.
• W2936942313 hasRelatedWork W3154255242 @default.
• W2936942313 hasRelatedWork W4313332089 @default.
• W2936942313 hasVolume "95" @default.
• W2936942313 isParatext "false" @default.
• W2936942313 isRetracted "false" @default.
• W2936942313 magId "2936942313" @default.
• W2936942313 workType "article" @default.