A combined lymphokine-activated killer (LAK) cell immunotherapy and adenovirus-p53 gene therapy for head and neck squamous cell carcinoma.

Background: The antitumor activity of lymphokine activated killer (LAK) cells immunotherapy is not always effective in all patients, especially when used alone. In this study, we investigated the in vitro antitumor activities of a combination of LAK immunotherapy and gene therapy employing an adenovirus carrying the p53 gene (Ad-p53) in human head and neck squamous cell carcinoma. Materials and Methods: The in vitro cytotoxicity of LAK cells was tested in H891 cells infected with or without Ad-p53, and the mRNA expression levels of natural killer group 2D ligands (UL16 binding protein (ULBP) 1 to 5) and tumor necrosis factor (TNF- α) in these cells were measured by real-time reverse transcription polymerase chain reaction. Results: Ad-p53 infection increased the cytotoxicity of LAK cells against H891 cells, and also increased the mRNA expression levels of the ULBPs in H891 cells and TNF-α in the LAK cells. Conclusion: The antitumor activities of LAK cells in H891 cells were enhanced by Ad-p53. Conclusion: The combinational therapy of LAK immunotherapy and Ad-p53 gene therapy may represent a new paradigm for the treatment of head and neck cancer. There has been significant improvement in the methods of cultivation for cytotoxic immune-effector cells. In the 1980s, lymphokine-activated killer (LAK) cells were generated by culturing of peripheral blood mononuclear cells (PBMCs) in the presence of interleukin-2 (IL2), and then cluster of differentiation 3 (CD3) antibody (OKT3), was used to enhance cell expansion (1). LAK cells demonstrated potent antitumor effects in animal models and in some clinical trials. LAK cells are mainly composed of natural killer cells (NK; CD3 - CD56 + ) and natural killer T-cells (NKT; CD3 + CD56 + ) cells, and they display major histocompatibility complex non- restricted antitumor activities. Although LAK cells have proven antitumor effects against various types of tumor cells (2, 3), in most clinical cases, the antitumor effect is rather modest when used alone. Therefore, we developed a novel combinational strategy to enhance the antitumor effect of LAK cells. Gene therapy with a recombinant adenovirus carrying the p53 gene (Ad-p53) has been investigated in many clinical trials worldwide (4, 5), and the State Food and Drug Administration (SFDA) of China approved Ad-p53 as the world's first commercialized gene therapy product in 2003. The intra- tumoral injection of Ad-p53 has recently been demonstrated to be safe, well-tolerated, and capable of local tumor control (6). Ad-p53 combined with radiation therapy significantly increased the 5-year locoregional tumor control rate, but not the 5-year overall survival rate, of patients with advanced nasopharyngeal carcinoma (7). The future goal in adenoviral cancer gene therapy is to develop a treatment regimen capable of systemic anti-tumor suppression to prolong the long-term survival of patients with advanced cancer.