Mong Cho

Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer

Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n = 30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.

Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis with Telbivudine or Adefovir: A Randomized Trial

BACKGROUND The efficacy of nucleoside and nucleotide analogues for hepatitis B has been linked to the magnitude and durability of hepatitis B virus (HBV) suppression. OBJECTIVE To compare the antiviral efficacy of telbivudine and adefovir dipivoxil, and the effects of switching from adefovir to telbivudine, in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B. DESIGN Randomized, controlled, open-label trial. SETTING 16 outpatient clinics. PATIENTS 135 treatment-naive, HBeAg-positive adults with chronic hepatitis B. INTERVENTION Patients were randomly assigned in a 1:1:1 ratio to 52 weeks of telbivudine (group A) or adefovir (group B), or 24 weeks of adefovir and then telbivudine for the remaining 28 weeks (group C). One hundred thirty-one patients completed 52 weeks of treatment. MEASUREMENTS The primary efficacy comparison was serum HBV DNA reduction at week 24, with a secondary comparison at week 52. RESULTS At week 24, mean HBV DNA reduction was greater in group A than in pooled groups B and C (-6.30 vs. -4.97 log10 copies/mL; difference, -1.33 log10 copies/mL [95% CI, -1.99 to -0.66 log(10) copies/mL]; P < 0.001), and more patients in group A were polymerase chain reaction-negative (39% vs. 12%; odds ratio, 4.46 [CI, 1.86 to 10.72]; P = 0.001). At week 52, the mean residual HBV DNA level was lower in group A and group C than in group B (3.01 log10 copies/mL [group A] and 3.02 log10 copies/mL [group C] vs. 4.00 log10 copies/mL [group B]; difference, -0.99 log10 copies/mL [CI, -1.67 to -0.32 log10 copies/mL] and -0.98 log10 copies/mL [CI, -1.64 to -0.32 log10 copies/mL]; P = 0.004). Adverse events were similar across groups; the most common were upper respiratory symptoms, headache, back pain, and diarrhea. LIMITATIONS The trial was open-label and was not of sufficient size or duration to compare clinical outcomes and long-term efficacy. CONCLUSION Telbivudine demonstrated greater and more consistent HBV DNA suppression than adefovir after 24 weeks of treatment. After 52 weeks, HBV DNA suppression was greater in patients who had received continuous telbivudine or were switched to telbivudine after 24 weeks than in those who received continuous adefovir.

Cancer‐Derived Lysophosphatidic Acid Stimulates Differentiation of Human Mesenchymal Stem Cells to Myofibroblast‐Like Cells

Lysophosphatidic acid (LPA) is enriched in ascites of ovarian cancer patients and is involved in growth and invasion of ovarian cancer cells. Accumulating evidence suggests cancer‐associated myofibroblasts play a pivotal role in tumorigenesis through secreting stromal cell‐derived factor‐1 (SDF‐1). In the present study, we demonstrate that LPA induces expression of α‐smooth muscle actin (α‐SMA), a marker for myofibroblasts, in human adipose tissue‐derived mesenchymal stem cells (hADSCs). The LPA‐induced expression of α‐SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA1 or LPA2 isoform expression with small interference RNA (siRNA). LPA elicited phosphorylation of Smad2/3, and siRNA‐mediated depletion of endogenous Smad2/3 or adenoviral expression of Smad7, an inhibitory Smad, abrogated the LPA induced expression of α‐SMA and phosphorylation of Smad2/3. LPA‐induced secretion of transforming growth factor (TGF)‐β1 in hADSCs, and pretreatment of the cells with SB431542, a TGF‐β type I receptor kinase inhibitor, or anti‐TGF‐β1 neutralizing antibody inhibited the LPA‐induced expression of α‐SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of α‐SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of α‐SMA and phosphorylation of Smad2. In addition, LPA increased the expression of SDF‐1 in hADSCs, and pretreatment of the cells with Ki16425 or SB431562 attenuated the LPA‐stimulated expression of SDF‐1. These results suggest that cancer‐derived LPA stimulates differentiation of hADSCs to myofibroblast‐like cells and increases SDF‐1 expression through activating autocrine TGF‐β1‐Smad signaling pathway.

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Clevudine is highly efficacious in hepatitis B e antigen‐negative chronic hepatitis B with durable off‐therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (e‐CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were −4.25 and −0.48 log10 copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log10 reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well‐maintained during the post‐treatment follow‐up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. Conclusion: A 24‐week clevudine therapy was well‐tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e‐CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission. (HEPATOLOGY 2007.)

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, β-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-naïve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumor-associated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically.

A prospective nationwide study of drug-induced liver injury in Korea.

OBJECTIVES:To address a growing concern about drug-induced liver injury (DILI), a nationwide study was performed to investigate the significance of DILI in Korea.METHODS:From May 2005 to May 2007, cases of DILI (alanine transferase >3 × upper normal limit or total bilirubin >2 × upper normal limit) from 17 referral university hospitals were prospectively enrolled. Adjudication by the seven review boards was considered for the confirmation of causality and the Roussel Uclaf Causality Assessment Method (RUCAM) scale was used.RESULTS:A total of 371 cases were diagnosed with DILI. The extrapolated incidence of hospitalization at university hospital in Korea was 12/100,000 persons/year. The causes included “herbal medications” (102, 27.5%), “prescription or non-prescription medications” (101, 27.3%), “health foods or dietary supplements” (51, 13.7%), “medicinal herbs or plants” (35, 9.4%), “folk remedies” (32, 8.6%), “combined” (30, 8.2%), “herbal preparations” (12, 3.2%), and others (8, 2.2%). Nine cases were linked to acetaminophen. The frequencies of hepatocellular, mixed, and cholestatic types were 76.3, 14.8, and 8.9%, respectively. A total of 234 cases met the criteria for Hys law. Five patients died or underwent transplantation. Twenty-five cases (21 herbs and 4 medications) did not meet the time-to-onset criteria of the RUCAM.CONCLUSIONS:DILI appears to be a highly relevant health problem in Korea. “Herbal medications” are the principal cause of DILI. A more objective and reproducible causality assessment tool is strongly desired as the RUCAM scale frequently undercounts the cases caused by herbs owing to a lack of previous information and incompatible time criteria.

Which types of stent, uncovered or covered, should be used in gastric outlet obstructions?

Background: Self‐expandable metallic stents (SEMS) have been widely used in inoperable malignant gastric outlet obstructions, but stent obstructions caused by tumor ingrowth and migration are a major problem of SEMS. The aims of this study were to assess the rate of stent restenosis, to identify lesion characteristics related to early restenosis by tumor ingrowth, and, in particular, to find suitable patient groups for uncovered or covered stents at first implantation. Methods: Forty‐nine patients were reviewed: stomach cancer in 34 patients, primary duodenal cancer in 3 patients, pancreatic cancer in 5 patients, and common bile duct cancer in 7 patients. In principle, uncovered stents were initially placed at the time when obstruction symptoms occurred and the endoscope would not pass through. Stent obstruction due to tumor ingrowth within 4 weeks after the first stent implantation was regarded as early stent restenosis. Results: Technical success was seen in 49/49 patients (100%). Migration did not occur. Stent obstructions caused by tumor overgrowth were found in 2/49 patients (4.1%) after 1 month. Stent obstructions caused by tumor ingrowth occurred in 14/49 patients (28.5%), and 7 of them (14.3%) were found to have early restenosis. The only statistically significant factor for early restenosis was stenosis site, and early restenosis was more frequent in the postoperative anastomosis site in the current study; a) 2/18 antropyloric obstructions (11.1%), b) 1/15 pyloric and duodenal bulb obstructions (6.7%), c) 0/10 duodenal second portion obstructions (0%), and d) 4/6 postoperative anastomosis site obstructions (66.7) (P < 0.05, 95% CI 0.003–0.005). Conclusions: Uncovered stents are technically feasible and effective for most malignant gastric outlet obstructions. However, because of frequent early restenosis among patients with postoperative anastomosis site obstructions, the placement of covered or simultaneous dual stents to prevent early restenosis should be considered when stenting postoperative anastomosis site obstructions.

Oncolytic and Immunotherapeutic Vaccinia Induces Antibody-Mediated Complement-Dependent Cancer Cell Lysis in Humans

The oncolytic and immunotherapeutic vaccinia virus Pexa-Vec (JX-594) induces antibody-mediated complement-dependent cancer cell cytolysis in rabbits and cancer patients, prolonging their survival. The Enemy of My Enemy Is My Friend: Virotherapy for Cancer Oncolytic viruses, which can kill cancer cells directly and by stimulating the patient’s immune system, have some clear advantages over other immune approaches to cancer treatment. They do not induce autoimmunity, they do not have to be custom-made for each patient, and they are not specific to tumors that express a particular antigen. Previous works with these viruses have shown promising results, and some of them are now in clinical trials. However, the steps by which these viruses exert their effects against the cancer cells in animals and humans are not yet fully understood. Now, the work by Kim et al. uncovers some of the mechanism for the action of Pexa-Vec, a vaccinia virus–derived oncolytic vaccine, which is already being tested in patients with multiple types of advanced cancers. In a rabbit model of squamous cell carcinoma, the authors demonstrated the induction of antibody-mediated complement-dependent cytotoxicity (CDC) after treatment with Pexa-Vec. The resulting antitumor activity could be transferred from one rabbit to another by transferring serum, even long after the virus was administered and then cleared from the blood, providing additional evidence for the role of antibodies. Serum from human patients treated with Pexa-Vec also induced CDC against cancer cells, primarily against cancer of the same type. For example, serum from a renal cancer patient treated with the virus was most effective at triggering CDC against renal cancer cells, consistent with a specific antibody-mediated process. The ability of each patient’s serum to induce CDC against cultured cancer cells correlated with that patient’s survival. Larger trials in human patients will be required to confirm the pilot study results presented here and build on the current understanding of oncolytic virotherapy and the role of CDC. In addition, further studies will need to investigate the role of other immune mechanisms, such as cell-mediated immunity, in the effects of oncolytic virus vaccines. In the meantime, the current study highlights the role of Pexa-Vec in the induction of antitumor CDC and shows its effects on survival, even in patients with late-stage cancer who have few other options. Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec–treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody–mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.

Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage

Vasoactive drugs are recommended to be started as soon as possible in suspected variceal bleeding, even before diagnostic endoscopy. However, it is still unclear whether the therapeutic efficacies of the various vasoactive drugs used are comparable. The aim of this prospective, multicenter, randomized, noninferiority trial was to characterize the effects of terlipressin, somatostatin, and octreotide when they are initiated before endoscopic treatment in patients with acute variceal bleeding. Patients with liver cirrhosis and significant upper gastrointestinal bleeding were randomly assigned to receive early administration of terlipressin, somatostatin, or octreotide, followed by endoscopic treatment. Patients with nonvariceal bleeding were excluded after endoscopy. The primary endpoint was 5‐day treatment success, defined as control of bleeding without rescue treatment, rebleeding, or mortality, with a noninferiority margin of 0.1. In total, 780 patients with variceal bleeding were enrolled: 261 in the terlipressin group; 259 in the somatostatin group; and 260 in the octreotide group. At the time of initial endoscopy, active bleeding was noted in 43.7%, 44.4%, and 43.5% of these patients, respectively (P = 0.748), and treatment success was achieved by day 5 in 86.2%, 83.4%, and 83.8% (P = 0.636), with similar rates of control of bleeding without rescue treatment (89.7%, 87.6%, and 88.1%; P = 0.752), rebleeding (3.4%, 4.8%, and 4.4%; P = 0.739), or mortality (8.0%, 8.9%, and 8.8%; P = 0.929). The absolute values of the lower bound of confidence intervals for terlipressin versus somatostatin, terlilpressin versus octreotide, and octreotide versus somatostatin were 0.095, 0.090, and 0.065, respectively. Conclusion: Hemostatic effects and safety did not differ significantly between terlipressin, somatostatin, and octreotide as adjuvants to endoscopic treatment in patients with acute gastroesophageal variceal bleeding. (Hepatology 2014;60:954–963)