Efficacy of cytokine‑induced killer cells targeting CD40 and GITR

Abstract

Since the publication of a novel protocol in 1991, cytokine-induced killer (CIK) cells have shown promising results in the treatment against neoplastic diseases. Despite ongoing preclinical and clinical studies, CIK cell treatment in the context of human monoclonal antibodies targeting tumor-necrosis factor receptors remains overlooked. The present study investigated whether a combination of CIK cells with human monoclonal antibody anti-CD40 and anti-Glucocorticoid-induced TNF-related protein (GITR) would lead to further cytotoxicity against tumor cells expressing CD40 and GITR ligand (L). Therefore, in vitro experiments with human lymphoma cell lines SU-DHL-4 and Daudi (both CD40 positive) and human breast adenocarcinoma MCF-7 (GITRL positive) were performed and the secretion of interferon (IFN)-γ was measured. Three interesting results emerged: i) a combination of CIK cells and anti-CD40 mAb is more effective than CIK cell treatment alone; ii) the use of anti-GITR mAb and CIK cells significantly enhanced the cytotoxicity of CIK cells against MCF-7 compared with single CIK cell treatment and iii) the combination of both antibodies and CIK cells abrogates the anti tumoral effect of CIK cells on all three cell lines. By performing an ELISA for IFN-γ measurement, a lower secretion was observed when anti-CD40 or anti-GITR mAb was added. This outcome indicates that further studies in vitro and in vivo may aid in understanding the synergistic molecular mechanisms of CIK cells, and anti-CD40 and anti-GITR mAb.

Cytokine‑induced killer cells/natural killer cells combined with anti‑GD2 monoclonal antibody increase cell death rate in neuroblastoma SK‑N‑SH cells

“…After cell harvesting, the proportion of CD3 + CD56 + (CIK) cells, CD3 − CD56 + (NK) cells and CD3 +/− CD56 + (CIK/NK) cells was detected by flow cytometry. The proportion of CIK cells are a group of immune effector cells characterized by the cell surface marker CD3 − CD56 + and the proportion of NK cells are a type of lymphocytes, which are distinguished by the cell surface marker CD3-CD56+ (39). Both CIK and NK cells play critical role in immune anti-tumor effect (40).…”

Clinical Studies on Cytokine-Induced Killer Cells: Lessons from Lymphoma Trials

“…Biederbick et al recently contributed to raise concerns about synergistic molecular mechanisms of CIK cells by using a combination of anti-CD40 and anti-GITR mAb in the human lymphoma cell lines SU-DHL-4 and Daudi (both CD40-positive) [ 60 ]. More recently, Li et al reported an increase in IFN-γ secretion in B-NHL cell lines treated with CIK alone or with the PD-1 antibody, yet this trend was not observed for PD-L1, raising the question of whether PD-1 and PD-L1 are comparable and interchangeable in the clinical practice [ 61 ].…”