Public Health

START Trial Will Show Whether Therapeutic Vaccine Stimuvax Has Potential To Extend Lung Cancer Survival Beyond Five Years

Of all cancers, non-small cell lung cancer (NSCLC) represents one of the greatest unmet needs for an effective and life-prolonging treatment. The condition, which accounts for 85 per cent of all lung cancers - roughly 1.4 million worldwide each year - is rarely diagnosed at its earliest and most potentially curable stage when it is amenable to surgical resection. Most patients are diagnosed when the tumour has already advanced to stage III, where it has invaded the chest tissues or mediastinal lymph nodes and is inoperable, or to stage IV where it has spread to other organ sites. Around 30 per cent are diagnosed at stage III and 40 per cent at stage IV. Both stages carry a poor prognosis. From stage III, and following chemo and radiotherapy treatment, median survival has been at best only between 13 and 18 months. Yet later this summer at the 13th World Conference on Lung Cancer in San Francisco, a leading researcher will report on a group of NSCLC patients who are still surviving up to eight years on from a Stage III diagnosis. Dr Charles Butts of University of Alberta, Edmonton, Canada, will reveal updated survival information on a small phase II clinical trial of 171 patients begun in 1998 investigating Stimuvax, an experimental therapeutic lung cancer vaccine (formerly known as BLP-25). Overall, the trial showed a survival benefit of a few months for patients randomised to receive the vaccine compared to best supportive care alone. But it also showed that a subset of patients with Stage IIIb locoregional (LR) disease did particularly well. When three-year survival data from the study were presented at the International Association for the Study of Lung Cancer congress in Seoul, South Korea, in 2007 they showed that of patients in this subset, those exposed to Stimuvax had a median survival of 30.6 months compared to 13.3 months if they did not receive the vaccine. Some of these patients are still alive today in 2009, almost eight years on from starting Stimuvax. This week Dr Butt"s reported on the long-term safety of the vaccine among patients using it for over two years at the American Society of Clinical Oncology (ASCO) meeting in Orlando, USA. Only minor side effects were reported, the most frequent being injection-site reactions and cough. The number of patients exposed to the vaccine was very small so no conclusions can be drawn from the research and no statistical significance can be attached to the promising results seen in this group of survivors. However, such was the promise shown in the phase II trial that a much larger phase III trial START (Stimulating Targeted Antigenic Responses To NSCLC) is now investigating the vaccine in many more patients - over 1300 in fact, all with Stage III NSCLC - and should give a definitive answer as to whether or not it really can improve chances of long-term survival for patients at this stage of disease (see link at end of this article for more information). Normally, only 5 to 7 per cent of Stage IIIb lung cancer patients achieve five-year survival but even patients in the control arm of the phase II Stimuvax study fared better than expected - a well-recognised bonus of clinical trial participation. The phase III START trial is currently recruiting patients with Stage IIIa or IIIb LR NSCLC who have already undergone, and responded to, chemotherapy and radiotherapy given at least a month earlier, or who have stable disease. The five-year survival rate for such patients would normally be in the range of 15 to 20 per cent. Over 250 centres in 30 countries are participating and the study should begin fielding results in a couple of years. How therapeutic vaccines work The role of therapeutic vaccines like Stimuvax in lung cancer is to stimulate the body"s own cancer-fighting res, the immune system, to reject cancer cells and prevent tumour growth, spread or recurrence. Following a primary tumour"s surgical removal, or after successful chemoradiotherapy when only minimal residual disease remains, a therapeutic vaccine could, theoretically, keep further disease at bay by encouraging the body to mount an immune response to mop up residual cancer cells and nip new cancer growth in the bud. The vaccine would stimulate the immune system to identify and destroy cancer cells expressing the antigen on which the vaccine is based. The idea is plausible but in the past therapeutic vaccine development has been fraught with problems and several have failed - some of them at the phase III stage, eg, Pfizer"s ProMune in advanced NSCLC. But the science of vaccine development has moved on in recent years, lessons have been learned, and there are now high hopes for a raft of new therapeutic vaccines from several companies in late stage development tackling NSCLC at different stages. Merck Serono"s vaccine Stimuvax is the most advanced of the vaccine candidates in development so far. It is based primarily around the mucin -1 (MUC-1) glycoprotein, a tumour-associated antigen discovered by Cancer Research UK (CRUK) in the late 1980s,and which is found on almost all cancer cells including NSCLC. Raj Mehta, Senior Business Manager at CR UK"s development and commercialisation arm, says the discovery made by scientist Joyce Taylor-Papadimitriou, now based at Guy"s and St Thomas"s Hospital, London, was an exciting one which was originally felt would be of most benefit to breast cancer patients. "MUC-1 is jelly-like stuff that appears to be involved in formation of the mucins lining the gut, lung and breast tissues. It keeps the epithelial cell surface moist," he explained. "Originally MUC-1 was named human milk fat globulin (HMFG) because it was found to be over-expressed in breast cancer". However when it was subsequently also observed in lung, pancreatic and prostate cancers, it was renamed MUC-1. In cancer it is thought it may play an unhelpful role in facilitating immunosuppression - the process by which tumours enable cancer cells to escape detection and destruction by the immune system - and in mediating resistance to anti-cancer agents. "MUC-1 is greatly over-expressed on tumours where it differs from MUC-1 on normal epithelial tissues in being abnormally glycosolated. This difference makes it ideal as a vaccine candidate because it is much more tumour-specific," Dr Mehta commented. A vaccine based on a protein occurring normally throughout the body could potentially risk setting up an auto-immune reaction where the body"s immune system rejects its own tissues. But this has not happened with the abnormally-glycosolated MUC-1 used in vaccine development. The immunogenic part of MUC-1 is a heavily glycosolated peptide core composed of a tandemly repeating sequence of 20 amino acids. This was licensed out as a 25 amino-acid peptide, BLP-25, by CR UK to Oncothyreon and in turn on to Merck Serono. The company has developed a lyophilised three-component vaccine, now called Stimuvax, consisting of the BLP-25 lipopeptide, the immunoadjuvant monophosphoryl lipid A, (MPL) and three other lipids (cholesterol, diyristoyl phospatidylglycerol, and dipalmitoyl phosphatidylcholine). MPL improves the immune response and the liposome delivery vehicle helps with antigen recognition and take up by antigen presenting cells. Cytotoxic T cell (natural cancer cell-killer) function is then enhanced with destructive effects on tumour cells. Although there are plans to test the vaccine in breast and prostate cancers, lung cancer is felt to be the first research priority on account of its huge unmet need for therapy. "Almost all NSCLC patients express MUC-1 on the surface of tumours but in phase II testing it has been the Stage IIIb patients who have shown the most eye-catching benefit in terms of survival from an anti MUC-1 vaccine strategy," Dr Mehta says. "This promise may not be borne out by the START trial but we are quietly optimistic. If the vaccine is proven to work in large numbers of patients it will be a breakthrough from a scientific as well as from a patient perspective. This is a seminal time for therapeutic cancer vaccines." The great advantage of vaccines like Stimuvax is that they are "off-the-shelf" peptide-based products that come in a vial and can be injected in any qualifying lung cancer patients, making therapy easy to carry out, he added. "They do not appear to have any serious side effects." Other vaccines are patient-specific, requiring whole cells taken from the patients" own tumours. These are returned to them after some ex-vivo manipulation designed to stimulate an immune response to a specific antigen. Treatment with Stimuvax involves first administering a single intravenous infusion of cyclophosphamide to reduce T cell suppressor activity followed three days later by one vial of the vaccine injected subcutaneously at 4 different sites: the deltoid or triceps muscles of the upper arm, and the left and right antero-lateral abdomen. This is carried out every week for eight consecutive weeks and then once every six weeks thereafter until disease progression occurs. Medical Oncologist, Professor Nick Thatcher of The Christie Hospital, Manchester, who is one of the START trial investigators believes patients who enrol in the trial are not put at risk of side effects or a deteriorating quality of life. "We have not seen anything to alarm us. Most side effects observed in early trials have been low-grade injection site reactions or flu-like symptoms," he told an audience of oncologists at a recent European meeting. In the phase II trial, 26 per cent of patients in the Stimuvax arm reported a serious adverse event (SAE) but even more (36 per cent) in the control group also reported an SAE. "SAEs were more related to the tumour than the treatment and few were rated grade 3 or higher" he noted "Quality of life was improved and maintained longer among patients receiving Stimuvax," he added. Dr Butts who led the phase II Stimuvax trial says: "No serious or life-threatening treatment-related

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