Natural Killer Cell Therapy: A New Treatment Paradigm for Solid Tumors

Abstract

In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Compared with cytotoxic T lymphocytes, NK cells take a unique position targeting tumor cells that evade the host immune surveillance by down-regulating self-antigen presentation. Recent findings highlighted that NK cells can even target cancer stem cells. The efficacy of allogeneic NK cells has been widely investigated in the treatment of hematologic malignancies. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. In allogeneic NK cell therapy, the mismatch between the killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) can be harnessed to increase the antitumor activity. However, the allogeneic NK cells cause more adverse events and can be rejected by the host immune system after repeated injections. In this regard, the autologous NK cell therapy is safer. This article reviews the published results of clinical trials and discusses strategies to enhance the efficacy of the NK cell therapy. The difference in immunophenotype of the ex vivo expanded NK cells resulted from different culture methods may affect the final efficacy. Furthermore, currently available standard anticancer therapy, molecularly targeted agents, and checkpoint inhibitors may directly or indirectly enhance the efficacy of NK cell therapy. A recent study discovered that NK cell specific genetic defects are closely associated with the tumor immune microenvironment that determines clinical outcomes. This finding warrants future investigations to find the implication of NK cell specific genetic defects in cancer development and treatment, and NK cell deficiency syndrome should be revisited to enhance our understanding. Overall, it is clear that NK cell therapy is safe and promises a new paradigm for the treatment of solid tumors.

Recent Advances in Molecular Mechanisms of the NKG2D Pathway in Hepatocellular Carcinoma

“…NKG2D is the most important activating receptor on the NK cell surface with quite a complex genetic structure and multiple protein functional sites. The specific binding of NKG2D to the high expression of MICA, MICB, and ULBP on the surface of hepatoma cells can trigger multiple signaling pathways, such as phosphatidylinositol 3-hydroxy kinase (PI3K), phospholipase C Gamma 2 (PLCã2), c-Jun-NH(2)-terminal kinase (JNK), and others, which also further promote the anti-tumor effects of NK cells by secreting cytokines, enhancing ADCC effects, and initiates the apoptosis process [108]. NKG2D ligands can be expressed individually and collectively on the surface of liver cancer cells.…”

A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy

“…Finally, a decrease of ADAM9 mRNA may indicate a candidate who can expect synergistic effects by adding adoptive cell therapy. Adoptive cell therapy composed of NK or CD8+ T cells have shown efficacy in treatment of HCC [3,17,22,[59][60][61]. However, the patient population who had survival benefits was mostly restricted to those with minimal tumor burden after treatments with curative modality [17,22,62].…”

“…Adoptive cell therapy composed of NK or CD8+ T cells have shown efficacy in treatment of HCC [3,17,22,[59][60][61]. However, the patient population who had survival benefits was mostly restricted to those with minimal tumor burden after treatments with curative modality [17,22,62]. Therefore, there remains significant room for improvement of the adoptive cell therapy in patients with high burden of HCC [17,22,62].…”

“…However, the patient population who had survival benefits was mostly restricted to those with minimal tumor burden after treatments with curative modality [17,22,62]. Therefore, there remains significant room for improvement of the adoptive cell therapy in patients with high burden of HCC [17,22,62]. This combination strategy may greatly enhance the survival of advanced HCC patients, as was shown in Subject #6.…”

“…These immunological features enable HCC to benefit from immunotherapy. Thus, harnessing these immune characters through combination immunotherapy is proposed as the next important step in treatment of advanced HCC [4,[13][14][15]21,22].…”