Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer

Abstract

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 -15.1months), median progressionfree survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.

Natural Killer Cells in Liver Disease and Hepatocellular Carcinoma and the NK Cell-Based Immunotherapy

“…In contrast, NK cells derived from a healthy donor (allogeneic) showed a positive response in AML patients [ 71 ], and the following studies also showed encouraging results by using haploidentical NK cells for both elderly and pediatric AML patients [ 72 – 74 ]. The clinical efficacy of the allogeneic NK cell adoptive immunotherapy to treat solid tumors has also been evaluated by several groups [ 75 – 77 ]. Lin et al had reported that percutaneous cryoablation combined with allogeneic NK adoptive transfer significantly increased the median progression-free survival of advanced HCC patients [ 75 ].…”

“…The clinical efficacy of the allogeneic NK cell adoptive immunotherapy to treat solid tumors has also been evaluated by several groups [ 75 – 77 ]. Lin et al had reported that percutaneous cryoablation combined with allogeneic NK adoptive transfer significantly increased the median progression-free survival of advanced HCC patients [ 75 ]. And multiple allogeneic NK cell infusion was associated with better prognosis in advanced cancers, including advanced HCC [ 75 ] and stage III pancreatic cancer [ 76 ].…”

“…Lin et al had reported that percutaneous cryoablation combined with allogeneic NK adoptive transfer significantly increased the median progression-free survival of advanced HCC patients [ 75 ]. And multiple allogeneic NK cell infusion was associated with better prognosis in advanced cancers, including advanced HCC [ 75 ] and stage III pancreatic cancer [ 76 ]. Allogeneic NK cell immunotherapy for advanced non-small-cell lung cancer also showed a significant benefit in clinic [ 77 ].…”

Cytotoxic immune cell-based immunotherapy for hepatocellular carcinoma

“…Encouraging clinical efficacy has been observed in trials of acute myeloid leukemia [110] . Moreover, cryoablation combined with allogeneic NK cell therapy markedly improved the progression-free survival of patients with advanced HCC [111] . Besides autologous and allogeneic NK cells, NK-92 cells, an NK cell line, is also used in clinical trials of cancer therapy, with encouraging results observed in patients with advanced lung cancer [112] .…”

Immunological Aspects of Cryoablation of Non–Small Cell Lung Cancer: A Comprehensive Review

“…50 This is of particular importance because tumor cells can downregulate surface MHC I expression as an immune escape mechanism to evade tumor-specific T cells. 51 Activated NK cells can also interact with DCs to improve DC tumor antigen uptake and presentation. 50 Furthermore, activated NK cells can produce proinflammatory cytokines (including interferon-g), which shift CD4-positive T cells toward T helper 1 cell-mediated immune responses and stimulate CD8-positive T cells to become CTLs, which are capable of destroying tumor cells.…”