Natural killer group 2D (NKG2D) receptor plays a pivotal role in cytokine-induced killer (CIK) cell-mediated cytotoxicity against malignancies, and the expression of NKG2D ligands might allow targets to be more susceptible to the CIK cell-mediated destruction. In this study, we investigated the synergistic effects of CIK cells antitumor activity and antibody-mediated inhibition of MICA/B shedding. This monoclonal antibody (7C6) has been previously shown to be able to specifically target MICA/B a3 domain on tumor cells, resulting in the increase in cell surface MICA/B expression by inhibition of their shedding. In the current study, we show that 7C6 antibody could substantially inhibit MICA shedding and stabilize the expression of MICA/B on Hela cells and MDA-MB-231 cells. In combination with 7C6, CIK cells showed higher degranulation rate, more IFN-γ production and elevated cytotoxic capacity against tumor cells. Furthermore, we demonstrate that NKG2D-MICA/B ligation could lead to activation of both CD3+ CD56− T cells and CD3+CD56+ NKT subset cells of CIK culture and NKT subset was more sensitive to NKG2D signaling than the counterpart T cells. 7C6-mediated inhibition of MICA shedding could strengthen this signal and eventually enhance the antitumor activity of CIK cells. With multiple advantages of easy ex vivo expansion, minor GVHD, natural tumor trafficking and non-MHC restricted, CIK cell-based therapy may serve as a potent combination partner with MICA antibody-mediated immunotherapy.

Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes that have acquired the expression of several natural killer (NK) cell surface markers following the addition of interferon gamma (IFN-γ), OKT3 and interleukin-2 (IL-2). Treatment with CIK cells demonstrates a practical approach in cancer immunotherapy with limited, if any, graft versus host disease (GvHD) toxicity. CIK cells have been proposed and tested in many clinical trials in cancer patients by autologous, allogeneic or haploidentical administration. The possibility of combining them with specific monoclonal antibodies nivolumab and ipilimumab will further expand the possibility of their clinical utilization. Initially, phenotypic analysis was performed to explore CD3, CD4, CD56, PD-1 and CTLA-4 expression on CIK cells and PD-L1/PD-L2 expression on tumor cells. We further treated CIK cells with nivolumab and ipilimumab and measured the cytotoxicity of CIK cells cocultured to renal carcinoma cell lines, A-498 and Caki-2. We observed a significant decrease in viability of renal cell lines after treating with CIK cells (p < 0.0001) in comparison to untreated renal cell lines and anti-PD-1 or anti-CTLA-4 treatment had no remarkable effect on the viability of tumor cells. Using CCK-8, Precision Count Beads™ and Cell Trace™ violet proliferation assays, we proved significant increased proliferation of CIK cells in the presence of a combination of anti-PD-1 and anti-CTLA-4 antibodies compared to untreated CIK cells. The IFN-γ secretion increased significantly in the presence of A-498 and combinatorial blockade of PD-1 and CTLA-4 compared to nivolumab or ipilimumab monotreatment (p < 0.001). In conclusion, a combination of immune checkpoint inhibition with CIK cells augments cytotoxicity of CIK cells against renal cancer cells.

Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.

Undeniably, immunotherapy has markedly improved the survival rate of cancer patients. The scenario is no different in lung cancer, where multiple treatment options are now available and the inclusion of immunotherapy yields better clinical benefits than previously used chemotherapeutic strategies. Of interest, cytokine-induced killer (CIK) cell immunotherapy has also taken a central role in clinical trials for the treatment of lung cancer. Herein, we describe the relative success of CIK cell therapy (alone and combined with dendritic cells as DC/CIKs) in lung cancer clinical trials and discuss its combination with known immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Additionally, we provide insights into the findings of several preclinical in vitro/in vivo studies linked to lung cancer. In our opinion, CIK cell therapy, which recently completed 30 years and has been approved in many countries, including Germany, offers tremendous potential for lung cancer. Foremost, when it is optimized on a patient-by-patient basis with special attention to the patient-specific genomic signature.