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Background: Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis., Methods: We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306., Findings: 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors., Interpretation: Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years., (Copyright © 2014 Corrie et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

We evaluated the safety and immunogencity of a novel vaccine directed against autologous TNFalpha in a Phase I fixed dose escalation trial. The vaccine consisted of two recombinant TNFalpha proteins, with specific peptides replaced by foreign immunodominant T cell epitopes from tetanus toxoid. The main objectives were to establish a safe dose and evaluate the vaccines ability to raise neutralising TNFalpha antibodies. Secondary objectives were improvements in body weight and tumour response. Thirty-three patients were vaccinated with three doses (20, 100, or 400 mug) of TNFalpha vaccine at 2-weekly intervals adjuvanted with aluminium hydroxide. Anti-TNFalpha antibody titres were measured by both a RIA, using soluble native TNFalpha as the antigen, and by an ELISA using immobilized partly denatured TNFalpha. Eleven patients (33%) had mild grade1/2 injection site reactions at the higher doses. In 10 of 20 patients, serum antibodies recognize denatured TNFalpha in the ELISA, whereas, antibody titres against native TNFalpha in the RIA were undetectable. This suggests that the production process had partly denatured the vaccine preventing the formation of cross-reacting antibodies to native TNFalpha. In conclusion, TNFalpha vaccine was able to elicit vaccine specific antibodies. However, since the antibodies were only able to cross-react with partly denatured TNFalpha, evaluation of safety and tumour responses to the TNFalpha vaccine was compromised.

Flaviviral diseases such as yellow fever, Japanese encephalitis (JE) and dengue hemorrhagic fever cause enormous morbidity and mortality worldwide. There is an urgent need for alternative technologies for mass vaccination against these and other diseases, particularly in the developing world. Here, we administered a live attenuated, chimeric JE vaccine (ChimeriVax)-JE) to nonhuman primates by skin microabrasion and intradermal delivery using microneedles. Both cutaneous delivery methods induced mild viremia similar in magnitude to that observed following subcutaneous (SC) injection. The duration of viremia induced by cutaneous delivery (5-7 days), however, was substantially longer than via SC (0-3 days). In addition, mean neutralizing antibody titers in cutaneous delivery groups were up to 7-fold greater than via SC injection. There were no safety issues identified and both cutaneous delivery methods appeared to be well tolerated. Thus, cutaneous delivery may represent a minimally-invasive alternative approach for flavivirus vaccines that more closely resembles the natural route of viral infection.

A new anthrax vaccine under clinical investigation is based on recombinant Bacillus anthracis protective antigen (rPA). Here, we investigated microneedle-based cutaneous and nasal mucosal delivery of rPA in mice and rabbits. In mice, intradermal (id) delivery achieved up to 90% seroconversion after a single dose, compared with 20% after intramuscular (im) injection. Intranasal (inl) delivery of a liquid formulation required 3 doses to achieve responses that were comparable with those achieved via the id or im routes. In rabbits, id delivery provided complete protection against aerosol challenge with anthrax spores; in addition, novel powder formulations administered inl provided complete protection, whereas a liquid formulation provided only partial protection. These results demonstrate, for the first time, that cutaneous or nasal mucosal administration of rPA provides complete protection against inhalational anthrax in rabbits. The novel vaccine/device combinations described here have the potential to improve the efficacy of rPA and other biodefense vaccines.

Colon cancer remains a major cause of death; however, in the last 3 years a number of trials have been published that have led to changes in the treatment of patients with this disease. Initially, the adjuvant treatment of patients following curative resection was based on their Dukes staging; this is now being refined by consideration of other pathological factors, as well as the investigation of newer prognostic markers such as p53, Ki67 and a number of genes on chromosome 18. Tumours generally develop from the progressive accumulation of genetic events, although some develop through mutation or inactivation of DNA mismatch repair proteins leading to microsatellite instability; this is particularly important in Lynch's syndrome. The loss of gene expression can occur by deletion or mutation of genes or by aberrant methylation of CpG islands. In patients with Dukes C colon cancer the standard of care for adjuvant chemotherapy was previously based on bolus fluorouracil (5-fluorouracil) and folinic acid (leucovorin) administered 5 days per month or weekly for 6 months. Recent studies with a combination of infusional fluorouracil, folinic acid and oxaliplatin have been found to be superior. A further study replacing fluorouracil with oral capecitabine has also demonstrated equivalent disease-free survival. Although some debate remains regarding the benefit of adjuvant treatment for patients with Dukes B colon cancer, the emerging consensus is that, for those patients who are younger and have high-risk features, chemotherapy should be discussed. A number of large vaccine trials have also been conducted in the adjuvant setting and, overall, these have been disappointing. This is a rapidly advancing area of therapy and the results of new trials are awaited to determine whether additional benefits can be achieved with biological therapies such as anti-vascular endothelial growth factor and anti-epithelial growth factor receptor monoclonal antibodies, which have already been shown to be effective in setting of metastatic colon cancer.

TNF is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases, but also in metastasis in certain types of cancer. In terms of therapy, TNF is targeted by anti-TNF neutralising monoclonal antibodies or soluble TNF receptors. Recently, a novel strategy based on the generation of self anti-TNF antibodies (TNF autovaccination) has been developed. We have previously shown that TNF autovaccination successfully generates high anti-TNF antibody titres, blocks TNF and ameliorates collagen-induced arthritis in DBA/1 mice. In this study, we examined the ability of TNF autovaccination to generate anti-TNF antibody titres and block metastasis in the murine B16F10 melanoma model. We found that immunisation of C57BL/6 mice with TNF autovaccine produces a 100-fold antibody response to TNF compared to immunisation with phosphate-buffered saline vehicle control and significantly reduces both the number (P<0.01) and size of metastases (P<0.01) of B16F10 melanoma cells. This effect is also observed when an anti-TNF neutralising monoclonal antibody is administered, confirming the essential role TNF plays in metastasis in this model. This study suggests that TNF autovaccination is a cheaper and highly efficient alternative that can block TNF and reduce metastasis in vivo and trials with TNF autovaccination are already underway in patients with metastatic cancer.

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in the pathogenesis of several chronic inflammatory diseases. Monoclonal antibodies against TNF-alpha are currently used for the treatment of rheumatoid arthritis and Crohn's disease. This report describes a simple and effective method for active immunization against self TNF-alpha. This vaccination approach leads to a T-cell-dependent polyclonal and sustainable anti-TNF-alpha autoantibody response that declines upon discontinuation of booster injections. The autoantibodies are elicited by injecting modified recombinant TNF-alpha molecules containing foreign immunodominant T-helper epitopes. In mice immunized with such molecules, the symptoms of experimental cachexia and type II collagen-induced arthritis are ameliorated. These results suggest that vaccination against TNF-alpha may be a useful approach for the treatment of rheumatoid arthritis and other chronic inflammatory diseases.