Purpose: Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC. Patients and Methods: In two prospective phase I studies, adult patients with advanced GPC3 þ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide-and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1). Results: A total of 13 patients received a median of 19.9 Â 10 8 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response. Conclusions: This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.

This study was aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with prostate cancer (PCa). A meta-analysis including 14 publications (15 cohorts) with 16,266 patients was performed to evaluate the association between NLR and overall survival (OS), progression-free survival (PFS)/recurrence-free survival (RFS) in PCa using hazard ratio (HR) and 95% confidence intervals (95% CI). The combining data showed that increased NLR predict poor OS (HR = 1.38, 95%CI: 1.22–1.56) and PFS/RFS (HR = 1.24, 95%CI 1.05–1.46) in PCa. Stratified analysis by PCa type, sample size, ethnicity and NLR cut-off value revealed that NLR showed consistent prognostic value in metastatic castration-resistant prostate cancer (mCRPC) patients and predict poor PFS/RFS in Asians, but not in Caucasians. These statistical data suggested that increased NLR could predict poor prognosis in patients with PCa.

This study was designed to explore the association between elevated platelet to lymphocyte ratio (PLR) and prognosis of patients with non-small cell lung cancer (NSCLC) by meta-analysis. A total of 11 studies with 3,430 subjects were included and the combined hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated. The data showed that elevated PLR predicted poor overall survival (OS) (HR = 1.42; 95% CI: 1.25–1.61, p < 0.001; I2 = 63.6, Ph = 0.002) and poor disease-free survival (DFS)/progression-free survival (PFS) (HR = 1.19; 95% CI: 1.02–1.4, p = 0.027; I2 = 46.8, Ph = 0.111). Subgroup analysis showed elevated PLR did not predict poor OS in patients included in large sample studies (HR = 1.44; 95% CI: 0.94–2.21, p = 0.098) whereas petients with Caucasian ethnicity (HR = 1.59; 95% CI: 1.27–1.98, p < 0.001) and PLR cut-off value >180 (HR = 1.61; 95% CI: 1.3–1.99, p < 0.001) had enhanced prognostic efficiency for OS. Subgroup analysis also demonstrated that high PLR did not predict poor DFS/PFS in Asian patients. In conclusion, our meta-analysis suggested that elevated PLR was associated with poor OS and DFS/PFS in NSCLC. In addition, high PLR especially predicted poor OS in Caucasians but had no association with poor DFS/PFS in Asians.

lncRNA-TUG1 (Taurine upregulated 1) is up regulated and highly correlated with poor prognosis and disease status in osteosarcoma. TUG1 knockdown inhibits osteosarcoma cell proliferation, migration and invasion, and promotes apoptosis. However, its mechanism of action has not been well addressed. Growing evidence documented that lncRNA works as competing endogenous (ce)RNAs to modulate the expression and biological functions of miRNA. As a putative combining target of TUG1, miR-144-3p has been associated with the progress of osteosarcoma. To verify whether TUG1 functions through regulating miR-144-3p, the expression levels of TUG1 and miR-144-3p in osteosarcoma tissues and cell lines were determined. TUG1 was upregulated in osteosarcoma tissues and cell lines, and negatively correlated with miR-144-3p. TUG1 knockdown induced miR-144-3p expression in MG63 and U2OS cell lines. Results from dual luciferase reporter assay, RNA-binding protein immuno precipitation (RIP) and applied biotin-avidin pull-down system confirmed TUG1 regulated miR-144-3p expression through direct binding. EZH2, a verified target of miR-144-3p was upregulated in osteosarcoma tissues and negatively correlated with miR-144-3p. EZH2 was negatively regulated by miR-144-3p and positively regulated by TUG1. Gain-and loss-of-function experiments were performed to analyze the role of TUG1, miR-144-3p and EZH2 in the migration and EMT of osteosarcoma cells. EZH2 overexpression partly abolished TUG1 knockdown or miR-144-3p overexpression induced inhibition of migration and EMT in osteosarcoma cells. In addition, TUG1 knockdown represses the activation of Wnt/β-catenin pathway, which was reversed by EZH2 over expression. The activator of Wnt/β-catenin pathway LiCl could partially block the TUG1-knockdown induced osteosarcoma cell migration and EMT inhibition. In conclusion, our results showed that TUG1 plays an important role in osteosarcoma development through miRNA-144-3p/EZH2/Wnt/β-catenin pathway.

3049 Background: HCC was commonly diagnosed and identified as leading causes of cancer death in China. Using a 10% cutoff score, GPC3 was detected in 63.6% of HCCs. Safety and preliminary efficacy of a GPC3 CAR-T was evaluated in 13 Chinese patients (pts) with r/r GPC3+ HCC in a Phase I trial. Methods: Pts between 18 and 70 yrs old with histopathological confirmed r/r GPC3+ HCC, Child-Pugh score≤B7, ECOG≤1, lymphocyte ≥ □0.7 x109, post-transduction positive T cells □ ≥30%, amplification by α CD3/CD28 ≥5 □, and without ascites and HIV infection were enrolled. Eligible pts undergo leukapheresis or whole blood colletion, which further developed into GPC3 CAR-T via lentiviral transduction. Standard release tests were conducted before administering GPC3 CAR-T in pts. Adverse events were graded per NCI CTCAE v.4.03. Efficacy was evaluated per modified RECIST (mRECIST). Results: All 13 pts, who received at least one infusion of GPC3 CAR-T, tolerated the treatment well. No dose-limiting toxicity (DLT) was identified, and only one SAE of grade 3 fever was reported. Preliminary analysis compared the clinical outcomes in pts who received GPC3 CAR-T without lymphodepleting conditioning (LDC) (Group A) vs. with LDC (Group B) at baseline. In Group A (N = 5), all pts developed progressive disease (PD) shortly after received a total infusion of GPC3 CAR-T ranging from 0.92x107 to 8.72 x107 cells/kg. In Group B (N = 8), following the LDC with fludarabine and cyclophosphamide, pts received a total infusion of GPC3 CAR-T ranging from 0.013x107 to 14.68 x107 cells/kg. Except two non-evaluable pts, the best response for the rest 6 pts are 1 PR, 3 SD, 2 PD. As of Feb 1, 2017, the PR pt remains alive for 385 days; 2 SD pts remain alive for 384 and 562 days, respectively; and one SD deceased at 108 days. Also worth to mention, one pt in Group A decided to remain on the study after PD, further received a total of 6.23 x107cells/kg infusions following a LDC given around Day 150, remains stable for 571 days as of Feb 1, 2017. Conclusions: Phase I trial shows GPC3 CAR-T is feasible and safe for Chinese pts with r/r GPC3+ HCC, and holds promising antitumor potential when LDC is applied along with GPC3 CAR-T. Clinical trial information: NCT02395250.

Crosstalk between competing endogenous RNAs (ceRNAs) is mediated by shared microRNAs (miRNAs) and plays important roles both in normal physiology and tumorigenesis; thus, it is attractive for systems-level decoding of gene regulation. As ceRNA networks link the function of miRNAs with that of transcripts sharing the same miRNA response elements (MREs), e.g. pseudogenes, competing mRNAs, long non-coding RNAs, and circular RNAs, the perturbation of crucial interactions in ceRNA networks may contribute to carcinogenesis by affecting the balance of cellular regulatory system. Therefore, discovering biomarkers that indicate cancer initiation, development, and/or therapeutic responses via reconstructing and analyzing ceRNA networks is of clinical significance. In this review, the regulatory function of ceRNAs in cancer and crucial determinants of ceRNA crosstalk are firstly discussed to gain a global understanding of ceRNA-mediated carcinogenesis. Then, computational and experimental approaches for ceRNA network reconstruction and ceRNA validation, respectively, are described from a systems biology perspective. We focus on strategies for biomarker identification based on analyzing ceRNA networks and highlight the translational applications of ceRNA biomarkers for cancer management. This article will shed light on the significance of miRNA-mediated ceRNA interactions and provide important clues for discovering ceRNA network-based biomarker in cancer biology, thereby accelerating the pace of precision medicine and healthcare for cancer patients.

The aim of this study is to assess whether preoperative serum interleukin-6 (IL-6) can predict recurrence of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC).The association between preoperative IL-6 levels and HCC recurrence following curative hepatectomy in 146 patients with chronic HBV infection was determined. Patients were divided into groups based on the presence or absence of HCC recurrence. Serum IL-6 levels were compared between groups, and the association between serum IL-6 level and greatest tumor dimension was also analyzed. Receiver operating characteristics (ROC) curve was used to define the optimal cutoff value for predicting recurrence-free survival (RFS) and overall survival (OS) rates. The OS and RFS rates were calculated using the Kaplan-Meier method.Out of 146 patients, 80 (54.8%) patients were documented as having HCC recurrence during the follow-up period. After adjusting for potential confounders, serum IL-6 levels were significantly associated with HCC recurrence, and a saturation effect existed with serum IL-6 levels up to 3.7 pg/mL. In addition, patients with preoperative serum IL-6 levels over 3.1 pg/mL had lower RFS and OS rates (P < 0.01). There was no significant correlation between preoperative serum IL-6 levels and maximal tumor dimension (r = 0.0003, P = 0.84).Elevated serum levels of IL-6 were significantly associated with an increased risk of HBV-associated HCC recurrence suggesting that preoperative IL-6 serum level is potential biomarker for early prediction of HBV-associated HCC recurrence.

PMWA is well tolerated in HCC patients and capable of offering high CA rate. Tumor number, tumor size, and AFP level were significant prognosticators of patients' PFS, whereas tumor size and AFP level were significant prognosticators of OS.