Iain McNeish, University College London
Ben - This week, we’re at the British Society for Gene Therapy’s annual conference in Brighton. One of the sessions looked at how gene therapy can be used to combat cancer; and the way researchers are trying to do it is by using viruses. Meera Senthilingam went to speak to Queen Mary University of London scientist Iain McNeish...
Iain - We talked about ovarian cancer and gene therapy using Adenoviruses in particular and our results show that ovarian cancers that have mutations in the genes BRCA1 and BRCA2 appear to be very sensitive to adenoviral gene therapy. Now, these two genes are mutated in around 40 to 50% of ovarian cancers and it means that women whose cancers have these mutations should be very sensitive to gene therapy, and obviously, these are the people we should be choosing to take part in our clinical trials. The other thing that we found is that ovarian cancers that are resistant to the chemotherapy drug Paclitaxel seem to be very sensitive to adenovirus and that raises two really interesting things: Firstly, resistance to chemotherapy - we found a whole new pathway whereby tumours can be resistant to chemotherapy that's never been described before. But also secondly, that if we treat people with Taxol first, then we should be treating them with adenoviruses afterwards. So, what I hope our result shows is that we found two obvious groups of patients who should be receiving gene therapy in clinical trials in the future, but also, it’s revealing new mechanisms of how the virus works, how chemotherapy might work, and how cancers can become resistant to it.
Meera - And what would the adenoviruses contain to actually target these cancers?
Iain - In fact, the adenoviruses contain nothing. So what we’ve done is we’ve taken a small part of the adenoviral genome out so that they now only replicate selectively within cancer cells. So, it makes them very, very simple to make because you're not putting new genes in. You're literally taking an ordinary virus, removing a small part of its DNA, and that makes it selective to kill cancer cells.
Meera - Why does it only replicate in cancer cells?
Iain - So the small part of the genome that we’ve removed interacts with a protein called retinoblastoma. We know that in cancer cells, retinoblastoma and the 10 other proteins that link with it are almost universally abnormal. So by taking these small little bits of DNA out, the virus can only replicate in cells that have an abnormal retinoblastoma pathway which is basically all cancer cells.
Meera - So this gets around any safety concerns about the virus spreading elsewhere?
Iain - In theory. Clearly, we haven’t put our virus into trials yet. However, a very similar virus was put into trial in the states last year in women with ovarian cancer and it’s still undergoing trials in people with brain tumours, and there’ve been no safety problems there are at all. Quite excitingly, showing that you can get anti-tumour efficacy by injecting similar viruses into people with ovarian cancer and brain tumours.
Meera - What actually causes the killing of these cancer cells, just purely the replication of the virus?
Iain - Ah, The billion dollar question, I think if we knew that! So, we think it’s probably multi-factorial, but viruses replicating within cells do kill them. But also, that killing triggers an immune response. So we think it’s probably at least two things: The direct killing of the cell by the virus but also, that sounding an alarm bell to the body’s immune system saying, “Come and kill me!” So, trials that we did a couple of years ago with a Herpes virus, we were able to demonstrate not only where we’re getting virus killing, but we were also getting immune cells coming into the tumour nodules, and we think that those two things combine to cause the overall effect.
Meera - In terms of what has been done so far, are there any figures as to just how effective this is in treating cancers?
Iain - Most adenoviruses are only at very early phase I, phase II [clinical trails]. The most famous adenovirus is the Onyx-015 virus which is now licensed in China – it’s called H101. It’s licensed for the treatment of head and neck cancer. So if you get head and neck cancer in China, you can get routinely treated with adenoviral gene therapy. The viruses that we work on, the second and third generation viruses are still in phase 1 and phase II trials. So, it would require another 3, 4, 5 years at least before we’re into big scale trials before we can say for certain whether they really will help people. Conceivably, within the next 5 to 10 years, gene therapy with adenoviruses could be routine care in this country.
Meera - But they are as to the lab and so they have been trialled in humans.
Iain - Yes, they have. So, there are lots of viruses in clinical trials, not just adenoviruses - reovirus, and vaccinia viruses. So, this is not just lab stuff. These are viruses that were being used to treat people with cancer right now. In clinical trials, yes so they're not yet licensed. They're still experimental but they're progressing from the lab towards the clinic and the patient.
Meera - And what's the real end goal? I guess, if the trials progress and results remain positive, is a hope that it would be the treatment of choice above current treatments or would it be say, that you would identify people resistant to Taxol and so on, and then result to this treatment?
Iain - Well, the end goal is that cancer gene therapy becomes a standard of care. It’ll be one of the options available to us, along with surgery, and chemotherapy, and radiotherapy. And the way we’re going to treat cancers in the future, the buzz expression is “personalised cancer medicine” is that we’re going to identify specific mutations and abnormalities in cancer and say, “Okay, you need to have this treatment and this treatment because your cancer has these mutations.” And if we found a virus that specifically targets cancer of abnormal RB pathway and defective homologous recombination in BRCA mutations then you say, “Okay, here is a treatment option for you.” So, it will be mixed in with other types of chemotherapy and radiotherapy, but it’ll just be another string to our bow to try and treat cancer.