The Royal Society of Edinburgh Joint lecture with the Scottish Cancer Foundation, supported by the Cruden Foundation

Vaccines to Prevent and Treat Cancer Professor Ian Frazer FRS CEO and Director of Research, Translational Research Institute, Brisbane, Australia 24 June 2013 Report by Jennifer Trueland
Sometimes described as Gods gift to women for his work in developing the HPV vaccine which aims to wipe out cervical cancer, Professor Ian Frazer gave some fascinating insights into the role that immunotherapy already plays in preventing and treating cancers as well as some glimpses to the future. If hed been asked to give this talk 20 or 30 years ago, said Professor Frazer, it would have been a very short lecture indeed; its only recently that weve known for sure that viruses cause cancer in humans. Likewise, using the immune system to prevent or treat cancer is a relatively new concept, but one in which there has been tremendous progress in the last two to three decades. In his lecture, Glasgow-born and Edinburgh-educated Professor Frazer outlined the 21st Century challenge of healthy ageing, explained why cancer is such an important target, and looked at what can be done to prevent and treat it. He focused in particular on the human papilloma virus (HPV), which causes cervical cancer, and on the vaccine (which he was instrumental in developing) that is already drastically reducing incidence of the disease in countries running immunisation programmes. Finally, he looked at the prospects for using immunotherapy to treat established HPV infection, and the challenges that remain. So why should we focus on cancer? In Australia, cancer is the most common cause of death, and there have been estimates that this will be the case worldwide by 2050. Around 70 per cent of cancer is preventable (with effort) and we can now cure around 50 per cent. Our chances of getting cancer depend on our genes (accounting for around 10 per cent of risk); what we do to ourselves, for example, smoking (30 per cent); what we do to the environment (30 per cent); and what we catch it from (30 per cent). Theres quite a list of things we can do to prevent cancer, he said, but the messages have tended to be confusing, and too full of thou shalt nots. For example, on one page of a newspaper it might say that coffee prevents cancer, while another page might say it causes it. Its not just about telling people what they need to do, he added, although he pointed out that behaviour modification is effective. For example, smoking accounts for around 40 per cent of avoidable cancer worldwide, obesity (in the developed world) around 10 per cent, and alcohol also around 10 per cent. If these avoidable cancers were prevented, then it would save around 30 per cent of healthcare costs and mean more money was available for medical research, and for treating the cases that remained. Immunotherapy, that is, using the immune system to tackle disease, is now an established component of cancer therapy. There are several approaches. These

include prophylactic vaccines, for example, hepatitis B and HPV, and using immunotherapy to treat cancers in practice, for example, Herceptin for breast cancer. Around 20 per cent of cancers are caused by infections, including papillomavirus, hepatitis B and C, and Epstein Barr virus. Focusing in particular on cervical cancer, he pointed out that it is a disease of the developing world. Over the years, there have been a number of theories about what causes cervical cancer; perhaps most notably (following a study comparing incidence among nuns to that among non-nuns, which found abnormal cells in the latter but not the former) that it is not caused by licentious behaviour but that the risk is greater among women who are excessively sensitive morally. It is now established, however, that cervical cancer is a rare consequence of chronic infection with papilloma viruses, which are transmitted sexually. Since it is a challenge to control infection, it is better to prevent it hence the search for a vaccine. [At this point Professor Frazer declared a potential conflict of interest, in that he and the University of Queensland benefit financially from the commercial sale of the prophylactic HPV vaccines discussed in the talk.] It was around 1980 that Harald zur Hausen found the viral link between HPV and cancer; he was disbelieved at first, but went on to win a Nobel Prize. HPV infection is common, and 95 per cent will resolve spontaneously, but around two per cent will progress to cancer over 15 years. Unusually, it is possible to detect pre-cancerous cells one to two years after infection it is these cells which are detected via screening programmes, when treatment will be effective in most cases. It took around 15 years to develop an HPV vaccine, in what Professor Frazer described as a billion-dollar process. Development of the vaccine was possible because of genetic engineering research, and was challenging in as much as it necessarily had to involve many thousands of people and a hard end point to prove efficacy, and even more to prove safety. Post-marketing surveillance has shown that from 44,000,000 doses over 24 months, 12,424 people reported possibly associated events, mostly non-serious, with fainting the most common. Adverse events in pregnancy were similar in both the vaccine and the placebo groups. Following the introduction and good uptake of the vaccine in Australia, the proportion of Australian-born women with genital warts fell markedly (in younger age groups). The proportion of heterosexual men diagnosed with genital warts also fell (across all age groups) suggesting that vaccinating women protects men (who were not vaccinated) too. Professor Frazer described a project to introduce an immunisation programme in Vanuatu, a group of islands off Australia with just five doctors for 250,000 people, one vaccine fridge, no reliable electricity, and high risk of HPV infection and associated pre-cancer. Immunisation was delivered as part of a programme which included educational sessions, aimed at parents, children, school staff and government. The people of Vanuatu were keen to protect their women, and uptake rates were high. Mothers tell their children: get this shot, he said. Bhutan, a poor country which values its health, did it too, largely down to influence from the royal grandmother, he added. Professor Frazer said the case for introducing immunisation programmes worldwide is compelling, adding that the evidence suggested it has a bigger impact in terms of benefit than the polio vaccine. But what about when the virus is already there? Professor Frazer said there is no evidence that cervical cancer vaccines are therapeutic for existing HPV vaccines. Despite promising results in the lab, it has to be borne in mind that mice lie, he

added. Immunotherapy [for existing HPV infection] might work in animals, but not in humans. Although, apparently, theres a good immune response to the vaccine, vaccination makes no change to colposcopy and histology. Researchers continue to work on several likely leads. For example, it would appear that adding inflammation to the mix could help mobilise the immune system to beat the virus. An early (Phase 1b) trial on patients with recurrent genital warts has shown that while the vaccine alone is ineffective, immunotherapy and inflammation works better than either alone. This is a basis for clinical trials, he added. A similar approach may also prove successful in treating squamous skin cancers, which are a major problem for Australia. The take-home message, he concluded, is that vaccines to prevent HPVassociated cancer should rapidly reduce disease burden where they are deployed, that immunotherapy for HPV infections may be possible, but epithelial immunology is focused on minimising damage and there are some technical barriers to overcome, and that embedding research in health practice is critical to moving forward with health care. Questions Asked about the issue of whether boys should be vaccinated against HPV, Professor Frazer said hed taken the decision to vaccinate his male children back in 2006. The Australian government has taken a similar decision this year. Although vaccinating girls does give a measure of protection to boys, this doesnt protect them overseas, for example. Boys deserve protection and there is a reasonable case for vaccination, he said. Asked whether there is evidence that the ability to clear the virus is associated with deprivation, Professor Frazer said that around two per cent of the population get persistent infection, but there is no evidence that environmental factors are at play it could just be random chance, he said. Responding to a question about the potential of vaccines for other cancers, Professor Frazer said that even the vaccines we have arent always used, and that we should be grateful for those, and make sure they are deployed. He said it costs pharmaceutical companies a huge amount to develop vaccines, and that some have been burned by vaccines which havent worked after years of investment. Asked to compare the value of screening and vaccination, Professor Frazer said both are important. Screening is relatively low tech, but with vaccination, youre acting now to see the benefits in 20 years time. Getting the message out there is important, particularly in areas such as subSaharan Africa, where groups such as the First Ladies Club which promote public health initiatives are influential. Build on the infrastructure that works, he said.

Vote of Thanks Professor Bob Steele of the University of Dundee thanked Professor Frazer for his masterly lecture and enormous contribution to human health worldwide.

Opinions expressed here do not necessarily represent the views of the RSE, nor of its Fellows The Royal Society of Edinburgh, Scotlands National Academy, is Scottish Charity No. SC000470