BACKGROUND. The anti-programmed cell death 1 (anti-PD-1) antibody pembrolizumab is clinically active against nonsmall cell lung cancer (NSCLC). In addition to T cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of patients with advanced NSCLC, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC. METHODS. In total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or higher were randomly allocated to group A (n = 55 patients given pembrolizumab plus NK cells) or group B (n = 54 patients given pembrolizumab alone). The patients received i.v. pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received 2 cycles of NK cell therapy as 1 course of treatment. RESULTS. In our study, patients in group A had longer survival than did patients in group B (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months; P < 0.05). In group A patients with a TPS of 50% or higher, the median OS and PFS was significantly longer. Moreover, the patients in group A treated with multiple courses of NK cell infusion had better OS (18.5 months) than did those who received a single course of NK cell infusion (13.5 months). CONCLUSION. Pembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1 + advanced NSCLC. TRIAL REGISTRATION. ClinicalTrials.gov NCT02843204.

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.

Vps4 is a host factor known to be involved in cellular vacuolar protein sorting. We report here that HBV replication and secretion can be significantly inhibited by Vps4 dominant negative, ATPase-defective, mutants K173Q and E228Q. In contrast, wild-type Vps4 at low dose can inhibit HBV replication more effectively in human hepatoblastoma cell line HepG2, than in human hepatoma cell line Huh7. To our knowledge, this is the first demonstration of an anti-HBV potential of dominant negative mutants of a protein sorting host factor Vps4.

In this study, the safety and clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for the treatment of advanced non-small cell lung cancer (NSCLC) were evaluated. From July 2016 to March 2017, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n = 30) and (2) the cryoablation combined with allogenic NK cell group (n = 30). The changes in immune function, quality of life, and clinical response were evaluated. We found that allogenic NK cells combined with cryosurgical treatment for advanced NSCLC have a synergistic effect, which not only enhancing the immune function of patients, improving the quality of life, and significantly increasing the response rate (RR) and disease control rate (DCR) compared to cryoablation group. This study is the first clinical trial of allogenic NK cells combined with cryosurgery for the treatment of advanced NSCLC and preliminaily its safety and efficacy.

Background/Aims: We evaluated the clinical effectiveness of irreversible electroporation (IRE) in combination with immunotherapy using allogenic natural killer cells (NK) for stage IV hepatocellular carcinoma (HCC). Methods: The study involved 40 patients with stage IV HCC who were divided equally into two groups: 1) simple IRE; and 2) IRE plus allogenic NK cells (IRE-NK); we mainly assessed the overall survival (OS). Results: The effect of the IRE-NK treatment was synergistic, i.e., not only did it enhance immune function, it also decreased alpha-fetoprotein expression and showed significantly good clinical effectiveness. At the median 7.6-month follow-up (range, 3.8–12.1 months), median OS was higher in the IRE-NK group (10.1 months) than in the IRE group (8.9 months, P = 0.0078). Conclusion: IRE combined with allogeneic NK cell immunotherapy significantly increases the median OS of patients with stage IV HCC.

Immunotherapy has limited efficacy against locally advanced pancreatic cancer (LAPC) due to the presence of an immunosuppressive microenvironment (ISM). Irreversible electroporation (IRE) can not only induce immunogenic cell death, but also alleviate immunosuppression. This study aimed to investigate the antitumor efficacy of IRE plus allogeneic γδ T cells in LAPC patients. A total of 62 patients who met the eligibility criteria were enrolled in this trial, then randomized into two groups (A: n = 30 and B: n = 32). All patients received IRE therapy and after receiving IRE, the group A patients received at least two cycles of γδ T-cell infusion as one course continuously. Group A patients had better survival than group B patients (median OS: 14.5 months vs. 11 months; median PFS: 11 months vs. 8.5 months). Moreover, the group A patients treated with multiple courses of γδ T-cell infusion had longer OS (17 months) than those who received a single course (13.5 months). IRE combined with allogeneic γδ T-cell infusion is a promising strategy to enhance the antitumor efficacy in LAPC patients, yielding extended survival benefits. ClinicalTrials.gov ID: NCT03180437.

Objectives The aim of the present study was to investigate the effects of strontium‐modified implant surfaces on promoting early bone osseointegration in osteoporotic rabbits. Materials and methods The surface topographies, chemical elements, contact angles and ionic releases of the SLA and SLA‐Sr samples were analysed by special instruments separately. Sixteen ovariectomized New Zealand rabbits received glucocorticoid administration, and sixteen SHAM rabbits were used as controls. After generating a successful osteoporosis‐induced model, SLA and SLA‐Sr implants were randomly inserted into the tibia and femur metaphysis of each animal. The rabbits were sacrificed after 3 and 6 weeks of bone healing, and then, removal torque values (RTVs), percentage of bone area (BA%) and percentage of bone‐to‐implant contact (BIC%) were analysed for the SLA‐Sr and SLA implants. Results Multiple nanostructures were found on the Sr‐incorporated titanium surface, and appropriate amounts of strontium ions from the SLA‐Sr surface were released into the surrounding tissue within 21 days. In vivo, SLA‐Sr implants displayed much more new bone around their surfaces than the SLA implants. Significantly higher RTVs and BIC% were observed for the SLA‐Sr implants than for the SLA implants in both osteoporotic (p < 0.01) and healthy animals (p < 0.01) at 3 and 6 weeks. The SLA‐Sr implants exhibited higher BA% in cortical bone (p < 0.01) and in cancellous bone (p < 0.05) than the SLA implants in osteoporotic rabbits at 3 weeks. Conclusions It is suggested that Sr‐incorporated surfaces treated through hydrothermal reactions have positive effects on promoting early osseointegration in both osteoporotic and non‐osteoporotic rabbits.

Emodin, an extracted natural compound from the root and rhizome of Rheum palmatum L, has been shown to have multiple biological activities including anticancer functions in previous studies. In this study, we investigated the anti-leukemic activity of emodin alone or emodin in the presence all-trans retinoic acid (ATRA) in acute myeloid leukemia (AML) cells and the potential signaling pathway involved. We demonstrated that emodin could significantly enhance the sensitivity to ATRA and present additive differentiation-inducing effects in AML cell line NB4 cells and, especially, in NB4-derived ATRA-resistant MR2 cells. Further study showed that increasing dose of emodin could effectively induce growth inhibition and apoptotic effects in both cell lines as well as in primary leukemic cells from AML patients. Moreover, the apoptotic induction in AML cells was associated with the activation of caspase cascades involving caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage. In addition, leukemic cell response to emodin stimuli in vitro was observed through the decreased expression levels of Bcl-2 and retinoic acid receptor α (RARα). Importantly, emodin was demonstrated as a new inhibitor of PI3K/Akt in AML cells, even in primary AML cells. It inhibited Akt phosphoration (p-Akt) at Ser473 as efficiently as mTOR at Ser2448. Consistently, it exerted suppression effects on the phosphoration of mTOR downstream targets, 4E-BP1 and p70S6K. Taken together, these findings indicate that emodin might be developed as a promising anti-leukemic agent to improve the patient outcome in AML.