Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer.

Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.

Allogenic Vγ9Vδ2 T cell as new potential immunotherapy drug for solid tumor: a case study for cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive and fatal tumor. CCA occurs in the epithelial cells of bile ducts. Due to increasing incidences, CCA accounts for 3% of all gastrointestinal malignancies. In addition to comprehensive treatments for cancer, such as surgery, chemotherapy, and radiotherapy, during the past few years, cellular immunotherapy has played an increasingly important role. As a result of our research, we have discovered the γδ T cell-based immunotherapy for CCA. CASE PRESENTATION: A 30-year-old male ( https://www.clinicaltrials.gov/ ID: NCT02425735) was diagnosed with recurrent mediastinal lymph node metastasis after liver transplantation because of Cholangiocarcinoma (stage IV). In the course of his therapy sessions, he only received allogenic γδ T cell immunotherapy from August, 2017 through February, 2018 (8 infusions in total). γδ T cells were expanded from peripheral blood mononuclear cells (PBMCs) of healthy donor, and ~ 4 × 108 cells were adoptive transferred to the patient. CONCLUSION: In the above case report of the Cholangiocarcinoma (stage IV) patient who had received liver transplantation and afterward was diagnosed with recurrent mediastinal lymph node metastasis, we clinically proved that allogenic γδ T cell treatment had no adverse effects. We observed that allogenic γδ T cell treatments positively regulated peripheral immune functions of the patient, depleted tumor activity, improved quality of life, and prolonged his life span. After 8 γδ T cell treatments, the size of lymph nodes was remarkably reduced with activity depletion. This clinical work suggested that allogenic γδ T cell immunotherapy could be developed into a promising therapy drug for CCA.

Iodine-125 seed implantation and allogenic natural killer cell immunotherapy for hepatocellular carcinoma after liver transplantation: a case report.

For advanced hepatocellular carcinoma (HCC) patients, liver transplantation (LT) is an optimal treatment with limitation of high risk of tumor recurrence related to the immunosuppressive chemotherapy as usually recommended. In this study, a 29-year-old man suffered from HCC recurrence after LT. He underwent radiotherapy (total dose: 45 Gy) but had no significant response. Then, he received iodine-125 seed implantation combined with allogenic natural killer (NK) cell immunotherapy. Liver function, immune function, circulating tumor cell counts and computed tomography scans were evaluated to determine the clinical effect. We found that this combined treatment produced enhanced immune function of the patient and reduction in tumor size. This is the first report of an efficacy and safety study about clinical regimen comprising allogenic NK cell immunotherapy combined with iodine-125 seed implantation for the treatment of HCC recurrence after LT.

Cetuximab combined with natural killer cells therapy: an alternative to chemoradiotherapy for patients with advanced non-small cell lung cancer (NSCLC).

Natural killer (NK) cells therapy has the potential to prolong survival in patients with advanced non-small cell lung cancer (NSCLC). We conducted a clinical trial to investigate the safety and efficacy of cetuximab plus NK cells therapy in patients with advanced NSCLC. Between June 2015 and August 2016, 54 patients with advanced EGFR-expressing NSCLC were assigned randomly to the cetuximab plus NK cells therapy group (A; n = 27) or cetuximab alone group (B; n = 27). Patients in group A received two courses of NK cells therapy continuously. Cetuximab was administered intravenously and the weekly maintenance dose was continued until tumor progression. All adverse effects were manageable and no significant difference was noted between the two groups (P > 0.05). Levels of CEA, NSE and circulating tumor cells (CTCs) in group A were significantly lower than those before treatment (P < 0.05). Patients in group A had a significant improvement in immune function and quality of life (QOL) (P < 0.05). Patients in group A survived longer than those in group B (median PFS: 6 months vs 4.5 months; median OS: 9.5 months vs 7.5 months; P < 0.05). Combination therapy could be an alternative to chemoradiotherapy for patients with advanced NSCLC.

Tumor cryoablation in combination with natural killer cells therapy and Herceptin in patients with HER2-overexpressing recurrent breast cancer.

In this study, we investigated the clinical benefits of a combination of tumor cryoablation with natural killer (NK) cells therapy and Herceptin for human epidermal growth factor (HER) 2-overexpressing recurrent breast cancer. From May 2015 to May 2016, 48 patients who met the enrollment criteria were assigned to three groups (n=16): cryoablation group (group I), cryoablation-NK cells therapy group (group II) and cryoablation-NK cells therapy-Herceptin group (group III). Safety and short-term effects were evaluated. All the adverse effects were manageable and acceptable. The three-therapy combination treatment not only yielded good clinical efficacy, it also improved the quality of life; reduced levels of circulating tumor cells (CTCs); reduced carcino-embryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) expression; enhanced immune function significantly. Furthermore, it can resulte in significant prolongation of progression free survival (PFS). This is the first clinical study to demonstrate the benefit of the three-therapy combination of tumor cryoablation, NK cells therapy, and Herceptin for HER2-overexpressing recurrent breast cancer.

Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer.

In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK) cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18) and allogeneic NK cells immunotherapy group (group II, n=18). The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC) level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3) expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer.

Clinical efficacy of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced non-small cell lung cancer.

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.

Effect of NK cell immunotherapy on immune function in patients with hepatic carcinoma: A preliminary clinical study.

We investigated the effectiveness of adoptive transfer of KIR ligand-mismatched highly activated nature killer (HANK) cells in patients with hepatic carcinoma. Peripheral blood mononuclear cells were obtained and cultured in vitro to induce expansion and activation of HANK cells. After 12 d of culture, the cells were divided into 3 parts and infused intravenously on days 13 to 15. The patients (n = 16) were given one to 6 courses of immunotherapy. No side effects were observed. The lymphocyte subsets and cytokine, thymidine kinase 1 (TK1) and circulating tumor cell (CTC) levels were measured 1 day before treatment and 1 month after the final infusion: the absolute number of total T cells and NK cells and the IL-2 and TNF-ß levels were significantly higher, and the TK1 and CTC levels were significantly lower at 1 month after treatment. The percentage of patients who experienced partial response, disease stabilization, and disease progression at 3 months after treatment was 18.8%, 50.0% and 31.2%, respectively. The total follow-up period was 2-12 months. The median progression-free survival from treatment was 7.5 months. This is the first study on the benefits of HANK cell immunotherapy for hepatic carcinoma These encouraging preliminary observations imply that HANK cell immunotherapy is safe, can improve the immune function of patients with liver cancer, and may even reduce the rate of tumor metastasis and recurrence. However, further studies on larger samples of patients with a longer follow-up period are required to confirm these findings.

Carcinoembryonic antigen as prognostic factor for metastatic non-small cell lung cancer by percutaneous cryosurgery.

Carcinoembryonic antigen (CEA) is a prognostic marker for early-stage non-small cell lung cancer (NSCLC), and cryoablation is a new therapeutic alternative for lung cancer. We determined whether cryoablation-induced changes in serum CEA levels correlated with tumor type (adenocarcinoma or squamous carcinoma) and treatment type (comprehensive therapy [cryoablation of all intra- and extrapulmonary tumors] or palliative therapy [cryoablation of only extrapulmonary tumors]) in patients with metastatic NSCLC, and assessed whether pre-treatment CEA levels predicted overall survival (OS). We retrospectively reviewed the clinical data of 88 patients with metastatic NSCLC who underwent comprehensive (62 patients) or palliative (26 patients) therapy. Pre- and post-cryoablation serum CEA levels and overall survival were determined for all patients. Cryoablation significantly reduced CEA levels in adenocarcinoma, but not squamous carcinoma, patients. Among adenocarcinoma patients, the cryoablation-induced reduction in CEA levels was significantly greater after comprehensive treatment than after palliative treatment; the OS of patients under comprehensive cryoablation was longer than those under palliative treatment. Among adenocarcinoma patients receiving comprehensive cryoablation, OS was significantly longer in those with normal pre-treatment serum CEA levels than in those with abnormal pre-treatment serum CEA levels. Pretreatment level and change of serum CEA can be a good indicator for therapeutic effects and OS in metastatic NSCLC patients under percutaneous cryosurgery.