Abstract
BackgroundDaratumumab (Dara), an anti‐CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells.MethodsWe analyzed CD38 and PD‐L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara.ResultsWe first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well‐known rapid depletion of natural killer cells. Finally, we found that PD‐L1 expression on antigen‐presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase.ConclusionOverall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD‐L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD‐L1/PD‐1 pathway in patients with MM.
Highlights
Targeting CD38 with the monoclonal antibody daratumumab (Dara) is a widely used treatment in the setting of relapsed or refractory multiple myeloma (MM).[1,2,3,4,5,6] Dara is currently approved, in combination with lenalidomide or bortezomib, for treatment of patients with MM who have received at least one prior line of treatment
In addition to the well-known rapid depletion of NK cells, we found that Dara progressively decreased plasmacytoid dendritic cells (pDC) which strongly expressed CD38
We found that while programmed cell death ligand 1 (PD-L1) expression is increased on peripheral dendritic cells (DC) and monocytes during VTD treatment, combination with the anti-CD38 monoclonal antibody Dara seems to prevent this phenomenon
Summary
Targeting CD38 with the monoclonal antibody daratumumab (Dara) is a widely used treatment in the setting of relapsed or refractory multiple myeloma (MM).[1,2,3,4,5,6] Dara is currently approved, in combination with lenalidomide or bortezomib, for treatment of patients with MM who have received at least one prior line of treatment. Chen et al[12] demonstrated that CD38 upregulation in tumor induces resistance to programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) blocking antibodies and coinhibition of CD38 and PD-L1 improves antitumor immune responses. This mechanism of immune resistance caused by CD38 provides an evident rationale to evaluate immunomodulatory effects of CD38 blockade by Dara on the PD-L1 expressing immune cells. We aimed to assess the immunomodulatory effects of Dara on CD38 expressing immune cells in the blood of STOCKER et al newly diagnosed MM patients receiving Dara based combination therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
