Ian Hampson is finding it hard to contain his excitement. A molecular virologist with a passionate interest in understanding the relationship between viruses and cancer, he thinks that he and his wife, Lynne, may – he stresses the word may – have found a revolutionary self-help therapy for women with pre-cancerous cell changes in the cervix.
Almost by chance, the Hampsons discovered in their lab at St Mary’s Hospital, Manchester, that the drug lopinavir, licensed for the treatment of HIV, attacks the strain of human papillomavirus (HPV) that causes virtually all cases of cervical cancer. An as-yet unpublished clinical trial has found that lopinavir capsules, when inserted into the vagina, appear to kill off abnormal cells in the cervix. There appear to be no side effects.
Cervical cancer is still the main killer of women in the developing world, causing more than 280,000 deaths worldwide annually, so the idea that women might use a simple vaginal pessary to protect themselves against it is an exciting prospect.
But the results of Dr Hampson’s trial are also promising for women in developed countries. Up to 40,000 women in England alone are found to have abnormalities of the cervix every year, following smear tests or biopsies. At present the only treatment for high grade, pre-cancerous changes is invasive – and far from risk-free – surgery.
Sensational news, then, but it has taken Dr Hampson 12 years and a battle against numerous obstacles – including UK red tape, lack of interest and funding – to reach this point. “Worldwide, one woman dies every two minutes of cervical cancer,” he says. “The results of the early trial are staggering, but I might have to wait another six months to get this study published, and another year to get a bigger study off the ground. I want to get this treatment on the road.”
The story begins in 2002, when Lynne, a lecturer in viral oncology at the University of Manchester, was studying HPV16 – the main cancer-causing strain of HPV – and analysing how human proteins interacted with virus proteins.
“It’s well known that viruses like HPV take over human cells by hijacking their ‘waste disposal systems’ to make cells throw away certain proteins inappropriately,” Dr Hampson says. “Human cells use enzymes called proteases to get rid of waste proteins in different ways. Lynne’s results suggested that HPV was enhancing the function of a specific type of protease.
“The findings made me speculate that there might be a drug that could selectively block this particular function of the virus. A class of drugs used to treat HIV, known as protease inhibitors, primarily targets the HIV protease enzyme; but previous work has shown they could also block the same type of human protease, which our results had shown was important for HPV. It was an epiphany.”
At his wife’s suggestion, they got hold of as many protease inhibitors as they could lay their hands on (using a national Aids repository in the US, which supplies small quantities of drugs for research). “We literally smashed up tablets and stuck them into cultures both of HPV and cervical cancer cells,” recalls Dr Hampson. Several seemed to have activity against HPV and cancer, but lopinavir was the most potent. “Lopinavir was remarkably toxic. We could see the cells dying in the lab.”
By 2011, he says, they had shown that lopinavir was “multifunctional”, meaning it inhibited both viral proteins and the proteins in cancer cells. Still nothing had been proven clinically, and as Dr Hampson soon discovered, setting up a patient trial proved difficult.
Lopinavir is made by the US company Abbott Laboratories as part of a combination drug for HIV called Kaletra. The good news was that, as one of the most widely prescribed drugs worldwide and already licensed for both children and adults with HIV, it would not need extensive safety testing. The bad news was that it was only licensed for oral delivery. This formulation would not, at the strength needed, get enough of the drug delivered to the cervix.
“Our work showed we needed a 10-fold higher concentration of the drug at the site of infection – the cervix – than you can get by taking the drug orally,” says Dr Hampson. “The obvious solution was to reformulate the drug, so it could be applied locally as a cream or pessary, and organise a clinical trial.”
But the cost of reformulating the drug meant there was little interest from drug companies, cancer charities or research agencies. Then one of Dr Hampson’s PhD students pointed out that one oral form of the drug available was a soft gelatin capsule, which might “melt very nicely” in the vagina, and could be trialled as a pessary.
There was another obstacle, though. In Europe the makers of the capsule had phased it out in favour of a hard tablet. A generic lopinavir capsule called Lopimune, made by an Indian company, was only licensed for Africa.
“I wanted to bring some Lopimune into the UK for a trial,” says Dr Hampson, “but it would have involved a lot of red tape – and would have cost a fortune. I felt as if I was banging my head against a brick wall.”
The same PhD student, Dr Orora Maranga, pointed out how useful such a self-help treatment – if it worked – would be to women in Africa, where there are few screening programmes to pick up pre-cancerous conditions, or surgical facilities to treat them.
So it was that, near the end of 2011, the Hampsons finally won approval from Kenyatta National Hospital in Nairobi (where Dr Maranga was then a senior registrar) for a preliminary trial of lopinavir in women with pre-cancerous cells in the cervix. In return they would set up a cervical-cancer screening programme – needed to identify women suitable for the trial – and facilities for surgery, if it was needed.
Funding such a trial was difficult, and Dr Hampson is enormously grateful to those who supplied money or equipment. Donors included St Mary’s, Central Lancashire Healthcare Trust, a company called Hologic, a UK philanthropist, Ken Cholerton, and a small charity on the Isle of Wight, the Caring Cancer Trust.
Finally, last year, in a trial overseen by Dr Maranga, more than 800 Kenyan women were screened for cervical cancer. Of those, 21 per cent were found to be HPV positive, of whom 40 had pre-cancerous cells in the cervix. Twenty-three of this group had high-grade disease – where there is a higher risk of cancer developing and for which the only treatment is surgery. A further 17 had low-grade or borderline disease.
All 40 women were asked to insert a lopinavir capsule as a pessary, twice a day, for two weeks. At three months, each participant underwent a biopsy of the cervix, together with a smear test. In 19 of the 23 women with high-grade disease, the abnormal cells had disappeared. Two women now had low-grade changes, while two still had high-grade disease, for which they needed surgery.
Dr Hampson emphasises that this was an early trial, the type normally used to look at how well a new drug is tolerated. And he points out that there were no side effects. “We had a 90 per cent treatment response in the high-grade group – we couldn’t believe it,” he says. Although high-grade disease can sometimes disappear spontaneously after a year or two, this is rare after three months. There was also, he reports, “very high clearance” among women with low-grade and borderline cell changes.
Dr Hampson is now planning a larger controlled trial involving 500-1,000 women based in three sites in Africa – Nairobi, Kampala and Johannesburg. If he can raise the funds, that is. If the results can be replicated, the advantages for women everywhere are obvious. This potential treatment, less invasive than surgery, would also avoid the risk of premature labour in pregnancy that is associated with the operation.
“Research has found that one surgical excision of abnormal cervical cells increases the risk of premature delivery by 14 per cent,” says Prof Pierre Martin-Hirsch, a gynaecology oncologist at Lancashire Teaching Hospitals, who finds the results of this first trial “impressive”.
By contrast, Dr Hampson points out that in cases where the disease is persistent, “treatment with lopinavir can be repeated as often as needed, because it appears to be safe.”
Lopinavir could also be an option for women with low-grade pre-cancers who are currently offered a “watch and wait” approach – “a horrible time of anxiety”.
“While a vaccine is now being offered against HPV in some parts of the world,” he points out, “it will take 20 to 30 years before we have immunity.”
Cancer Research UK says it cannot comment on a trial that has not yet been peer-reviewed or published. “This is raising the hopes of patients,” warns a spokesman. “A peer review might find flaws in the trial. It may never get published.”
What frustrates Dr Hampson is the fact that, even if further trials were successful, it could be years before this pessary becomes available. There is now talk of of a “window trial” – one in which lopinavir could be offered to women with high-grade disease while they are waiting for surgery. “The drug has been shown to be safe, and the women have nothing to lose and everything to gain. If it works they will not need an operation.
“We are looking at this possibility, but clinicians in the UK are understandably cautious about using treatments off-label. And who can blame them? In our litigation culture, it doesn’t pay to take risks.”
Which is why Dr Hampson supports Lord Saatchi’s Medical Innovation Bill, designed to encourage doctors to innovate without fear of prosecution, and which is the subject of a government-backed consultation.
“At present there is a great reluctance to deviate from the accepted best clinical practice. Had we been able to obtain the particular drug formulation in the UK, it would have been far easier to convince a clinician to try the treatment – if the fear of litigation was reduced.”
The University of Manchester has filed a patent for treatment with lopinavir for HPV-related disease
Saatchi’s Medical Innovation Bill
Lord Saatchi’s Bill, now open to public consultation, would allow doctors to prescribe ‘’off label’’ drugs. These are drugs that have been tried and tested for one specific use (in this case lopinavir used to combat HIV). lopinavir is known to be safe, but doctors cannot easily prescribe it for other, non-standard uses. The Bill aims to speed up the development of new and innovative treatments for cancer and other diseases.
The Caring Cancer Trust has agreed to accept donations towards funding a phase 3 trial of lopinavir for pre-cancerous cell changes in the cervix. More details are available from their Virgin Money Giving page which can be accessed from their website http://www.caringcancertrust.com/