Abstract
CD123 (IL-3Rα) is frequently expressed by malignant Hodgkin lymphoma (HL) cells. Naked monoclonal antibodies (mAb) against HL lack clinical benefit, partially due to absence of natural killer (NK) cells in the tumor microenvironment. Here we show that the combination of a fully humanized anti-CD123 mAb (CSL362) and high-affinity Fcγ-receptor NK-92 cells (haNK) effectively target and kill HL cells in vitro. First, we confirmed high expression of CD123 in 2 of the 3 HL cell lines (KM-H2 and L-428), and its absence in NK cells. Cytotoxicity of haNK cells against CD123-positive HL cells was significantly higher in the presence of CSL362. This was also shown with IL-15-activated primary NK cells, although haNK cells showed a 10.87-fold lower estimated half-maximal stimulatory effective concentration (EC50). CSL362 facilitated a significant increase in the expression of CD107a, intracellular IFN-γ and TNF-α and enhanced expression of c-JUN, PLD-1, and ARF6 by NK cells. Inhibition of the ARF6–PLD-1 axis (NAV2729), but not of the MAPK pathway (U0126), completely abrogated CSL362-facilitated antibody-dependent cell-mediated cytotoxicity (ADCC) in haNK and activated primary NK cells. Our results support CD123 as an immunotherapeutic target for HL and the combination of NK cells and CSL362 as a treatment strategy for HL.
Highlights
Despite increasing survival rates, about 15–25% of the patients with Hodgkin lymphoma (HL) die because of progressive disease[1]
Gating on CD56+ cells, predominant expression of CD16+ was confirmed on highaffinity Fcγ-receptor NK-92 cells (haNK) cells (93.4%) to a level similar to primary Natural killer (NK) cells isolated from peripheral blood
CD16-positive NK cells and the fully humanized anti-CD123 monoclonal antibodies (mAb) CSL362 is highly active against CD123-expressing HL
Summary
About 15–25% of the patients with Hodgkin lymphoma (HL) die because of progressive disease[1]. Natural killer (NK) cells are either absent or present in only very small numbers in the HL tumor microenvironment[5]. NK cellmediated antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism contributing to clinical efficacy of most monoclonal antibodies (mAbs) in cancer patients[10,11,12]. The lack of sufficient NK cells in the HL tumour microenvironment may explain the failure of naked mAbs targeting CD30, the most prominent tumor antigen of malignant HL cells, to achieve positive outcomes in phase I–II clinical trials[13,14,15]. Our group and others have shown that cellular therapy with allogeneic NK cells is feasible and safe, and clinically relevant responses can be achieved against a variety of malignancies[20,21,22,23].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
