A prospective investigation into the effect of colchicine on tuberculous pericarditis.

INTRODUCTION: Tuberculous (TB) pericarditis carries significant mortality and morbidity rates, not only during the primary infection, but also as part of the granulomatous scar-forming fibrocalcific constrictive pericarditis so commonly associated with this disease. Numerous therapies have previously been investigated as adjuvant strategies in the prevention of pericardial constriction. Colchicine is well described in the treatment of various aetiologies of pericarditis. The aim of this research was to investigate the merit for the use of colchicine in the management of tuberculous pericarditis, specifically to prevent constrictive pericarditis. METHODS: This pilot study was designed as a prospective, double-blinded, randomised, control cohort study and was conducted at a secondary level hospital in the Northern Cape of South Africa between August 2013 and December 2015. Patients with a probable or definite diagnosis of TB pericarditis were included (n = 33). Study participants with pericardial effusions amenable to pericardiocentesis underwent aspiration until dryness. All patients were treated with standard TB treatment and corticosteroids in accordance with the South African Tuberculosis Treatment Guidelines. Patients were randomised to an intervention and control group using a web-based computer system that ensured assignment concealment. The intervention group received colchicine 1.0 mg per day for six weeks and the control group received a placebo for the same period. Patients were followed up with serial echocardiography for 16 weeks. The primary outcome assessed was the development of pericardial constriction. Upon completion of the research period, the blinding was unveiled and data were presented for statistical analysis. RESULTS: TB pericarditis was found exclusively in HIV-positive individuals. The incidence of pericardial constriction in our cohort was 23.8%. No demonstrable benefit with the use of colchicine was found in terms of prevention of pericardial constriction (p = 0.88, relative risk 1.07, 95% CI: 0.46-2.46). Interestingly, pericardiocentesis appeared to decrease the incidence of pericardial constriction. CONCLUSION: Based on this research, the use of colchicine in TB pericarditis cannot be advised. Adjuvant therapy in the prevention of pericardial constriction is still being investigated and routine pericardiocentesis may prove to be beneficial in this regard.

Application of interferon modulators to overcome partial resistance of human ovarian cancers to VSV-GP oncolytic viral therapy.

Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response.

Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency.

As cancer treatment tools, oncolytic viruses (OV) have yet to realize what some see as their ultimate clinical potential. In this study, we have engineered a chimeric vesicular stomatitis virus (VSV) that is devoid of its natural neurotoxicity while retaining potent oncolytic activity. The envelope glycoprotein (G) of VSV was replaced with a variant glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP), creating a replicating therapeutic, rVSV(GP), that is benign in normal brain but can effectively eliminate brain cancer in multiple preclinical tumor models in vivo. Furthermore, it can be safely administered systemically to mice and displays greater potency against a spectrum of human cancer cell lines than current OV candidates. Remarkably, rVSV(GP) escapes humoral immunity, thus, for the first time, allowing repeated systemic OV application without loss of therapeutic efficacy. Taken together, rVSV(GP) offers a considerably improved OV platform that lacks several of the major drawbacks that have limited the clinical potential of this technology to date.

Semireplication-competent vesicular stomatitis virus as a novel platform for oncolytic virotherapy.

Among oncolytic viruses, the vesicular stomatitis virus (VSV) is especially potent and a highly promising agent for the treatment of cancer. But, even though effective against multiple tumor entities in preclinical animal models, replication-competent VSV exhibits inherent neurovirulence, which has so far hindered clinical development. To overcome this limitation, replication-defective VSV vectors for cancer gene therapy have been tested and proven to be safe. However, gene delivery was inefficient and only minor antitumor efficacy was observed. Here, we present semireplication-competent vector systems for VSV (srVSV), composed of two trans-complementing, propagation-deficient VSV vectors. The de novo generated deletion mutants of the two VSV polymerase proteins P (phosphoprotein) and L (large catalytic subunit), VSVΔP and VSVΔL respectively, were used mutually or in combination with VSVΔG vectors. These srVSV systems copropagated in vitro and in vivo without recombinatory reversion to replication-competent virus. The srVSV systems were highly lytic for human glioblastoma cell lines, spheroids, and subcutaneous xenografts. Especially the combination of VSVΔG/VSVΔL vectors was as potent as wild-type VSV (VSV-WT) in vitro and induced long-term tumor regression in vivo without any associated adverse effects. In contrast, 90% of VSV-WT-treated animals succumbed to neurological disease shortly after tumor clearance. Most importantly, even when injected into the brain, VSVΔG/VSVΔL did not show any neurotoxicity. In conclusion, srVSV is a promising platform for virotherapeutic approaches and also for VSV-based vector vaccines, combining improved safety with an increased coding capacity for therapeutic transgenes, potentially allowing for multipronged approaches.