Quanli Gao

Association of myeloid-derived suppressor cells and efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma patients.

Metastatic renal cell carcinoma (MRCC) is one of the malignancies that are sensitive to immunotherapy. However, the underlying immune inhibitory factors such as myeloid-derived suppressor cells (MDSCs) might restrain the efficacy of immunotherapy. The present study investigates the clinical efficacy of cytokine-induced killer (CIK) cell therapy in patients with MRCC and explores whether the levels of peripheral MDSCs are associated with the prognosis of patients receiving this therapy. Twenty-nine patients with measurable MRCC were treated with an adoptive transfer of autologous CIK cells, followed by 5 consecutive days of interleukin-2 administration. The tumor response and 1-year survival were observed. The proportion of MDSCs in the peripheral blood was detected, and the correlation of MDSCs with prognosis was analyzed. Of 29 evaluable patients, no complete responses were seen; 4 patients exhibited a partial response (13.8%), 18 patients displayed stable disease (62.1%), and 7 patients showed progressive disease (24.1%). Twenty patients (69.0%) were alive 14.8–41.4 months at the time of the last follow-up (median follow-up=20.2 mo). The 1-year survival was 82.8% (24/29). Peripheral blood MDSCs were elevated in almost all MRCC patients and decreased after CIK-cell infusion. Subgroup analysis indicated that patients with a relatively low proportion of MDSCs exhibited prolonged survival. In conclusion, our data suggest that transfusion of autologous CIK cells can induce regression of MRCC, and MDSCs can serve as a potential marker for the prognosis of patients receiving a CIK-based therapy.

MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer

Adoptive immunotherapy using cytokine-induced killer (CIK) cells is a promising cancer treatment, but its efficacy is restricted by various factors, including the accumulation of myeloid-derived suppressor cells (MDSCs). In this study, we determine whether chemotherapeutic drugs that reduce MDSC levels enhance the efficacy of CIK cell therapy in the treatment of solid tumors. Fifty-three patients were included in this study; 17 were diagnosed with metastatic renal cell carcinoma (MRCC), 10 with advanced pancreatic cancer (PC), and 26 with metastatic melanoma (MM). These patients were divided into two groups: CIK cell therapy alone and CIK cell therapy combined with chemotherapy. Combining CIK cell therapy and chemotherapy increased 1-year survival rates and median survival times in MRCC and PC patients, but not in MM patients. The disease control rate did not differ between treatment groups for MRCC or MM patients, but was higher in PC patients receiving combined treatment than CIK cell treatment alone. These data suggest that addition of MDSC-decreasing chemotherapy to CIK cell therapy improves survival in MRCC and PC patients.

Linc00210 drives Wnt/β-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner

BackgroundLiver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown.MethodsLncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1.ResultsUsing transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/β-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/β-catenin activation. Linc00210 silencing cells showed enhanced interaction of β-catenin and CTNNBIP1, and impaired interaction of β-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/β-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/β-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation.ConclusionWith copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/β-catenin signaling. Linc00210 interacts with CTNNBIP1 and blocks the combination between CTNNBIP1 and β-catenin, driving the activation of Wnt/β-catenin signaling. Linc00210-CTNNBIP1-Wnt/β-catenin axis can be targeted for liver TIC elimination.

Efficacy of RetroNectin-Activated Cytokine-Induced Killer Cell Therapy in Metastatic Brain Tumor Patients

Background: The aim of this study was to investigate the clinical efficacy of RetroNectin-activated cytokine-induced killer cell (R-CIK) therapy following conventional therapies in patients with metastatic brain tumors. Methods: This study included 20 patients with metastatic brain tumors. Patients received R-CIK therapy following conventional therapies (including chemotherapy and target therapy). Progression-free survival (PFS), overall survival (OS), and prognostic factors were evaluated. Results: Of the 4 breast cancer patients in our cohort, 2 remained alive and 2 died. Of the 14 non-small cell lung cancer (all adenocarcinoma) patients, 3 had a partial response, 8 had stable disease, and 3 had progressive disease after receiving R-CIKs. The overall response rate was 21.4% (3/14), and the disease control rate was 78.6% (11/14). The median PFS and OS were 7.7 months (95% confidence interval (CI) 3-16.5 months) and 12.6 months (95% CI 6-21 months), respectively. Conclusion: R-CIKs combined with conventional therapies could improve the prognosis of metastatic brain tumor patients, especially of those with adenocarcinoma of the lung.

Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells

Adoptive cell therapy (ACT) using autologous cytokine-induced killer (CIK) cells is a promising treatment for metastatic carcinomas. In this study, we investigated the impact of RetroNectin on the proliferation, phenotype alternation, cytokine secretion, and cytotoxic activity of CIK cells from pancreatic cancer patients. Furthermore, we treated 13 patients with metastatic or locally advanced pancreatic cancer using autologous RetroNectin-activated CIK cells (R-CIK cells) alone or in combination with chemotherapy. Compared with only CD3 activated CIK cells (OKT-CIK cells), R-CIK cells showed stronger and faster proliferative ability, with a lower ratio of spontaneous apoptosis. Moreover, this ability continued after IL-2 was withdrawn from the culture system. R-CIK cells could also secrete higher levels of IL-2 and lower levels of IL-4 and IL-5 versus OKT-CIK cells. There was no difference between OKT-CIK and R-CIK cells in cytotoxic ability against lymphoma cell line K562. In patients who received auto-R-CIK cell infusion therapy, the overall objective response rate was 23.1%. Median survival time (mOS) after first R-CIK cell infusion was 10.57 months; the 1-year survival rate was 38.5%. No serious toxicity was associated with R-CIK cell infusion. In conclusion, RetroNectin may enhance antitumor activity of CIK cells: it is safe for use in treating pancreatic cancer.

Angiogenesis inhibitors rechallenge in patients with advanced non-small-cell lung cancer: a pooled analysis of randomized controlled trials.

Purpose Data on the role of angiogenesis inhibitors (AIs) rechallenge in the treatment of advanced non-small-cell lung cancer (NSCLC) patients who previously received bevacizumab remain limited. We aim to investigate the efficacy of AIs in the treatment of advanced NSCLC in this setting. Methods Studies from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology meeting up to December 1, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials evaluating AIs in advanced NSCLC, with survival data on patients who previously received bevacizumab. The end points were overall survival and progression-free survival. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies. Results A total of 452 patients with advanced NSCLC who previously received bevacizumab were identified for analysis. The meta-analysis results demonstrated that AI rechallenge significantly improved progression-free survival (hazard ratio: 0.72, 95% confidence interval: 0.58–0.89, P=0.002) when compared to non-AI containing regimens. Additionally, a nonsignificant improvement in overall survival was also observed in advanced NSCLC in this setting (hazard ratio: 0.82, 95% confidence interval: 0.65–1.03, P=0.087). Similar results were also observed in subgroup analysis according to treatment regimens. Conclusion The findings of this study suggest that NSCLC patients who relapsed after a first-line bevacizumab-containing chemotherapy obtain improved clinical benefits from AI rechallenge. Prospective clinical trials investigating the role of AI rechallenge in this setting are recommended.

Platelet-to-lymphocyte ratio in peripheral blood: A novel independent prognostic factor in patients with melanoma

Objectives: This retrospective study aimed to investigate the prognostic value of pre‐treatment platelet‐to‐lymphocyte ratio (PLR), which is an inflammatory indicator, in patients with melanoma. Methods: Patients in this retrospective analysis were admitted between January 1, 2010 and December 31, 2015 in Henan Cancer Hospital. Receiver operating characteristic (ROC) curve was performed the optimal cut‐off value for PLR. The 140 patients were divided into two groups: high PLR group and low PLR group. The relationship between PLR and overall survival (OS) was analyzed. The Kaplan‐Meier and Log rank tests were used for univariate survival analysis and Cox proportional hazards regression model for multivariate analysis. Results: The optimal cut‐off value of PLR determined by ROC curve was 120.15. Univariate and Cox multivariate survival analysis all showed that PLR and clinical stage were factors affecting OS in melanoma patients (P < 0.05). The overall median OS was 21.0 months (95% confidence interval (CI): 18.1–23.9), for 17.0 months in the high PLR group, and 34.0 months in the low PLR group (hazard ratio: 0.436, 95% CI: 0.291–0.652, P < 0.001), respectively. Clinical subgroup analysis showed that PLR was a risk factor in patients with stage II, III, and IV disease (P < 0.05). Conclusion: The elevated PLR was an independent prognostic predictor for OS in patients with melanoma.

Survival benefit from RectroNectin-activated cytokine-induced killer cells combined with chemotherapy in advanced EGFR wild-type lung adenocarcinoma

AIM To investigate the efficacy of chemotherapy and RectroNectin-activated cytokine-induced killer (R-CIK) cell immunotherapy in patients with advanced EGFR wild-type lung adenocarcinoma. METHODS Using data gathered from a single institution, 125 patients with stage IIIB or IV EGFR wild-type lung adenocarcinoma between January 2009 and June 2015 were identified and enrolled in this retrospective study. RESULTS The disease control rates and median overall survival was better in R-CIK group compared with control group. Multivariate survival analysis showed that R-CIK cell treatment was an independent prognostic factor for overall survival. CONCLUSION R-CIK cell immunotherapy may prolong survival of patients with advanced EGFR wild-type lung adenocarcinoma.

TGFβ1-induced down-regulation of microRNA-138 contributes to epithelial-mesenchymal transition in primary lung cancer cells

The existence of cancer stem cells within the tumor could lead to cancer therapy resistance. TGFβ1 is considered as one of the most powerful players in the generation of CSCs through induction of epithelial-mesenchymal transition in different types of cancer including lung cancer, however, the detailed mechanisms by which TGFβ1 contribute to EMT induction and CSC maintenance remains unclear. Here, we showed primary lung cancer cells treated by TGFβ1 exhibit mesenchymal features, including morphology and expression of mesenchymal marker in a time-dependent manner. We also observed long-term TGFβ1 exposure leads to an enrichment of a sub-population of CD44+ CD90+ cells which represent CSCs in lung cancer cells. Moreover, the differential expression microRNAs between CSCs and non-CSCs were identified using next-generation sequencing to screen key miRNAs which might contribute to TGFβ1-induced EMT and CSCs generation. Among those differentially expressed miRNAs, the expression of microRNA-138 was time-dependently down-regulated by TGFβ1 treatment. We further demonstrated primary lung cancer cells, in which we knockdown the expression of miR-138, exhibit mesenchymal phenotypes and stem cell properties. Taken together, these findings indicate TGFβ1-induced down-regulation of microRNA-138 contributes to EMT in primary lung cancer cells, and suggest that miR-138 might serve as a potential therapeutic target.

Treatment of relapsed/refractory (R/R) B-cell malignancies by chimeric antigen receptor T cells cultured from 50-100 mL peripheral blood in 7-10 days.

7034Background: Anti-CD19 chimeric antigen receptor (CAR) T cells for R/R B-cell malignancies has been remarkably effective in recent clinical trials. However, the training process is complex and l...