Every once in a while I see a paper that makes me sit up and say “Wow”. They are rare, but when they happen they let us really see the progress that is being made. This week one of those papers was published in the journal Science Translational Medicine.The study built on recent work that is focused on the immune system, and the potential that we can make it attack a cancer (something which doesn’t normally happen). There has already been some excellent results in this field in human trials, but this study took the work in a slightly different direction. The work was carried out in mice, so is still at an early stage, but the a small clinical trial is starting this month, and that will tell us how optimistic we should be.What these scientists have developed is a clever way to activate the immune cells specifically within the tumour by injecting it with a tiny amount of DNA and another compound. When they did this they found that the tumours shrank and disappeared. It gets better though: they tried the same approach in breast cancer, colon cancer, and melanoma, (three very different cancer types) and saw the same effect across the board.
Perhaps the most exciting part of the work was that when they injected one tumour, the immune system attacked all the tumours in that mouse, which means that this is an approach that may work in late stage patients, who are typically very difficult to treat.The technique itself makes use of a trick that is already used in patients: by injecting a tiny amount of DNA into a patient’s cancer, we can improve responses to chemotherapy. It works by making the immune cells in the vicinity express a marker on their surface, which has the effect of priming them for action. The insight that these scientists had, was that by using a second compound to recognize this marker, they could activate the cells to attack the tumour. Because the injection is directly into the cancer, only the immune cells that recognize the tumour are activated. Some of these then leave the original tumour and attack other ones throughout the body.This approach proved to be remarkably effective. In total, the scientists treated 90 animals with the therapy. Eighty seven of those were cured. Additionally, in some of the mice the tumours became resistant and began to grow again, which is typically what happens in human patients. However, if they then injected this new tumour with the therapy, they saw the same shrinking as before, which is extremely encouraging.It was a startlingly successful study, but as I mentioned above, this work was in mice, so we can’t be sure the results will translate to humans. It’s possible that there will be toxicity to humans, or that there will be issues with stimulating the immune system like this, but it is also very possible that we will see some real benefits of this therapy.It’s an exciting time to be in cancer research!
Using stem cells to treat cancer
There are many scam artists around nowadays proclaiming the benefits of their particular unproven stem cell therapy, for anything from curing cancer to making paralysed people walk again. It’s not surprising really; stem cells are a pool of cells in every organ that are almost eternally youthful and can regenerate themselves and all other cells in the organ. They sound almost magical. However, last year the FDA (the US Food and Drug Administration) had to move to crack down on these clinics, citing the of lack of evidence that any of them work and a number of serious complications reported following treatment. Complications including patients in Florida dying, a woman developing bone fragments in eyelids following a stem cell facelift, and another developing nasal tissue in her spine after a doctor promised to cure her paralysis with stem cells.It is a field ripe for abuse partly because it is one with so much potential. Stem cells do have fascinating possible applications, and there is a lot of research going in to them at the moment. Unfortunately, most exposure people have with them is in science fiction or alternative medicine. Which is why it was very interesting to see a study published last week that underlined how much real potential this field of research has. The study used mice instead of humans, so is still at an early stage, but is very promising nonetheless.Scientists from North Carolina were studying a deadly form of brain cancer called glioblastoma (GBM), which has extremely poor prognosis for patients diagnosed with it. The work builds on the bizarre finding that these tumours somehow attract stem cells to them. So if you look at a GBM in humans, there are stem cells inside them that shouldn't be there. Scientists had previously used this fact to load some stem cells with chemotherapy and could show that in mice, the stem cells were attracted by the tumour as expected, but they could also release their therapy while they were there. The problem with this is that we have very few stem cells in the brain so finding them and loading them with drugs is very difficult.In this case the scientists overcame that problem by turning skin cells into brain stem cells. They took skin cells from mice into the lab and, because skin cells originally comes from the spinal cord which is technically part of the brain, were able to trick them into reverting back into that state. They could then give these cells their chemo payload and inject them back into the mice. When they did this the stem cells made their way to the brain and reduced tumour size to almost nothing, which is obviously a very impressive response.There are two key advantages of this approach: 1) we have lots of skin stem cells, so they are easy to get; and 2) you can do it with a patient’s own cells, meaning that you wouldn’t have to worry about rejection, which can cause severe complications. This work still has to undergo significant testing to ensure it is safe for humans, but studies so far have been positive. A group in California have carried out a clinical trial which showed that apart from tissue rejection (which isn’t an issue in this case), stem cells can be a remarkably safe form of therapy.This work is still at an early stage, but it is very encouraging. Considering that the average survival time for a patient with GBM is only a year, any new therapeutic avenues are welcome. The stem cell field is one that is on the cusp of large-scale application, and this could be one of the first in an array of new therapies for cancer and many other diseases. At present however, 95% of clinics offering these therapies are charlatans looking to make money off vulnerable people.
Why screening is hard
It’s a simple fact that the most effective thing we can do to cure more cancers is to catch them earlier. If we find bladder cancer at an early stage, the five year survival is 88%; if we catch it at a late stage, when it has started spreading around the body, it drops below 15%. This is why we screen for certain diseases, including breast, bowel and cervical cancer. These large-scale screening programs are the best hope we have for majorly reducing the toll cancer takes on our lives.Screening, however, is hard. The main problem we face is accuracy. An ideal test would flag up 100% of sick people and 0% of healthy people. However, these tests are never perfect. There is always a percentage of sick people who are not flagged up (false negatives) and a percentage of healthy people who are incorrectly labelled as sick (false positives). And these problems can get pretty bad pretty quickly.The following diagram illustrates this issue. It shows the results of a test that is quite accurate (one that has 90% accuracy) applied to a common disease that is present in 1% of the population.
As you can see above, what sounds like a good screening test results in 10 times more false positives than true positives, while it also tests one person as negative while they are actually positive.In a large population, even a small percentage of error translates into a large number of misidentified patients. This can result in a crippling financial burden on the health system, as well as unnecessary worry, stress and pointless treatment for perfectly healthy people.As a result, only extremely accurate tests can be used in the clinic, which is the reason we screen for so few diseases. So how do we get around this? Well, obviously we have to develop more accurate tests, and a lot of effort is currently being invested in this field.Additionally, we can also improve things by being more selective about the people we screen. If a disease is present in 1% of the general population, but present in 5% of people over 65, then we can screen just the over 65s.So using the above the example of a test with 90% accuracy, if the prevalence is 5% instead of 1%, then rather than 10-times more false positives than true positives, there is just over 2-times. If the test were 98% accurate, then we would have far more true positives than false positives. This increased accuracy in a specific population is what we are working towards.
However, while significant research is being carried out in the development of new tests, it is disappointing to note that this is still a small percentage of cancer research funding. According to the National Cancer Research Institute, in 2011 (the most recent year I could find numbers for), research into early detection, diagnosis and prognosis received just 12.6% of cancer research funding.While it is understandable that research into a “cure” is more attractive than research into early diagnosis, the potential benefits of early diagnosis far outstrip that of drug development. Encouragingly, this level of funding is increasing steadily, and rose from 8.1% in 2002 to 12.6% in 2011. If this research can result in more viable screening programs, this will provide a significant clinical benefit to cancer patients.For more information about screening, I’d recommend having a look at the sense about science website, which does a great job of describing not just this problem, but also many others that arise in screening populations for diseases.
Recent advances in cancer therapy
First off, sorry for the lack of writing in the last few weeks; I’ve been in the middle of a job hunt, so my time has been limited by that. In the time I have taken off however, there have been some major news stories about cancer.The week of the 15th February brought some pretty sensational headlines. These were about a trial of a new immunotherapy, which both The Times and the Independent proclaimed “a cure”, and The Guardian labelled as “unprecedented”.Immunotherapy is an extremely promising branch of cancer therapy that has recently been getting a lot of attention. I have previously written about it here, so I won’t go into detail about how exactly it works. Simply put, it involves taking some of a cancer patient’s immune cells, teaching them to recognise the tumour, and then putting them back into the patient. These immune cells can now identify the cancer, attack it, and hopefully clear it from the system.
These results have not been published yet (they were presented at a conference), so we can’t say for sure how reliable they are. We do know however, that the trial had just 36 patients on it, and that it was looking at a cancer we can already treat with a high degree of success (acute lymphoblastic leukaemia (ALL)), so the headlines were far more sensational than the work deserves. That being said, it does appear to be a very encouraging study. However, as I have previously written, claiming something is a “cure” for cancer is likely to be wrong.This treatment appears to be very effective for ALL, and it may eventually become part of the standard therapy for this disease. However, ALL is just one of a large number of different types of cancer. Couple this with the ability of the disease to develop resistance to therapy and it becomes unlikely that this (or any other therapy) will ever be a “cure” for cancer. So while this is certainly an exciting advance, claiming it is a cure is unfortunately incorrect. It may have the potential to cure some patients, but without long term testing, we just don't know if this is the case.This problem of resistance brings me to the second big cancer story that’s been in the news recently. Coincidentally, it is also to do with immunotherapy. In this study, scientists found that a patient’s cancer carry markers that the immune system could be primed to attack, as I described above.However, it has always been assumed that as a tumour develops, it would change and evolve, resulting in some cells that no longer have these markers, and would therefore be resistant to the immune cells taught to target those markers. What is interesting about this study is that the scientists showed that this may not always be the case, and that all of a patient's tumour cells may still carry the markers, meaning they would all be attacked by the immune system. The video below (from CRUK) describes this very nicely.https://www.youtube.com/watch?v=ZPwrvPerxIkThe potential that a patient won't develop resistance to a therapy is one that scientists and doctors can only hope for. If this study holds, and is extended to other cancers, this dream may become a reality for some people. Again, this is a study on very few patients, but it gives us a tantalising glance at a potential weakness in cancer that could be exploited.It is an exciting time to be a cancer researcher!
A new technique to tackle malaria?
This week brought news of a fascinating new approach to preventing malaria. Malaria is an illness caused by a parasite that is spread by mosquitos and causes 219 million illnesses per year, and 500,000 deaths.
This statistic however, doesn’t convey the extent of a problem malaria poses. It is a disease that kills vulnerable people in countries least equipped to tackle it: 90% of those deaths occur in sub-Saharan Africa, and shockingly almost 80% occur in children under 5 years old (400,000 deaths).Furthermore, economically, it is thought to impact the GDP of some countries by up to 5 – 6% per year (Nigeria and the DRC for example). To put that into context, the same problem in the UK would cost the country around £120 billion; the entire annual budget of the NHS is £95.6 billion.It is easy to see how this disease is financially ruinous for sub-Saharan Africa, and how big an affect fewer cases of malaria could have.This is why it is big news that a strain of mosquito that is resistant to the parasite (and thus cannot spread the disease) has been created in the lab.The scientists introduced a gene into the DNA of the mosquitos, one that gives the insect an antibody against the malaria parasite. This antibody causes the insect’s immune system to kill the parasite. In tests, the researchers found no transmission of the disease by these mosquitos.This is an impressive feat in itself; however on its own it isn’t much use. This is because every individual has 2 copies of every gene, and only one copy is transmitted to the offspring. So normally the modified mosquito would pass its copy of the resistance gene to half its offspring (see figure, below). They in turn will pass it to half their offspring, and so on. Very soon the resistance gene would be naturally drowned out of the population.This is where a second bit of technology comes into play. The scientists took advantage of something called a Gene Drive, a system aimed at forcing the expansion of a gene in a population using Crispr/Cas9 technology, Crispr/Cas9 is a system with the ability to snip out and replace bits of genes, which Myriam has previously blogged about here. Using this approach, they resistant gene could actually snip out the “unresistant” second copy and replace it with a copy of itself.This way, when the modified mosquito passes the resistance gene to its offspring, the unresistant second gene from the other parent gets replaced by another copy of resistant one. As a result, ALL the offspring inherit the malarial resistance (see figure, below). This resistance would then become more and more common, theoretically reducing the incidence of malaria in humans.
At present there are no plans to release the resistant mosquitos into the wild however. We are, in effect, forcing genetic changes on an entire species, driving its evolution in a particular direction. This could have very unpredictable ecological consequences, as was emphasised in a warning recently published in the journal Science.Additionally, the technology isn’t quite ready yet, but it is only a matter of time before it is. When it is actually ready, we will be presented with a difficult question: considering how devastating malaria is in sub-Saharan Africa, is it ethical to delay the release of this gene drive because of these ecological concerns?This question obviously doesn’t have a simple answer. It is something governments and the science community will have to thrash out in the coming years.
Tracking tumours with blood samples
This week, a couple of new studies (which can be found here and here) showed that we can track changes in a tumour through blood samples alone. To understand the importance of this it is worth knowing that chemotherapy is going through a radical change at the moment.
The last few years have seen the introduction of a new generation of cancer drugs. These are targeted therapies, ones that are targeted not only towards a specific cancer but also towards specific sub-types of that cancer, based on the mutations that they have in their DNA. Not only are these chemotherapies more effective, but they should also cause fewer side effects than ones used in the past. Several of these targeted therapies have proven to give remarkable responses, with tumours melting away better than we could have dreamed.However, as patients have taken these drugs, an unfortunate pattern has emerged: the patients show amazing responses for a few months, but pretty quickly resistance emerges and the tumours regrow, now insensitive to the therapy.In fact, the very specificity of these drugs is actually their Achilles heel. Because they are designed to target a specific mutation in a specific gene, if certain other mutations occur in the same gene, they can result in resistance to the therapy (for an example of this, see below).It is in this background that the studies mentioned above could prove very important. These studies showed that simply by looking at the blood of patients, the scientists could track what mutations were happening in the tumour. This is because cancers shed lots of DNA into the blood stream, and the researchers could detect and analyse this. They showed that they could track the tumour as it developed, looking at what new mutations were arising. In effect, they could predict resistance to a drug before it became apparent in the patient. Not only that, but they could see how the resistance was happening and suggest alternative therapies that may be effective.This is all very good news. Previously, the only way of doing this was to take a biopsy of the tumour itself, a very invasive procedure that carries its own risks, and one that cannot be carried out regularly. With this new method, we will hopefully be able to monitor the tumour much more closely (patients shouldn’t object to giving blood every couple of weeks), and be proactive in treatment, rather than reactive.This method is still too expensive to be made commonly available, but the cost is rapidly decreasing, and it should be accessible in the near future. Additionally, with the move in cancer treatment towards targeted therapy, this will hopefully majorly increase the effectiveness of our new generation of therapies. Example of resistance to a targeted therapyA drug designed for some lung cancers was targeted towards a specific mutation in a pro-growth protein called EGFR. In these cancers, EGFR was stuck in the “on” position as a result of the mutation, which meant it was driving uncontrolled growth. The drug was specifically developed to turn this protein off again, which resulted in it hitting the cancer, and largely leaving other cells unaffected. This therapy worked beautifully in patients for 10 – 14 months, but resistance appeared after that and we were back to square one in our options for treatment. When they looked at the new, resistant tumour, scientists found that the resistant cells had picked up additional mutations in EGFR, activating it in a different way. As a result, the cells were resistant to our targeted therapy.
The cost of a cancer breakthrough
A new combination of drugs marketed by Bristol-Meyer Squibb has been hailed as a breakthrough in cancer treatment. Almost every media outlet carried a story about the results of a trial that were announced at a conference in Chicago yesterday, with the usual hype. The results are quite remarkable. 58% of metastatic melanoma patients treated with this new drug combination saw their tumours shrink, with the tumours stable or shrinking for a median of 11.5 months. This is amazing when you consider that metastatic melanoma was thought to be largely incurable as recently as 5 years ago. The drugs are each a form of immunotherapy. This refers to a therapy that works by making the patient’s own immune system attack the tumour. In this case, the combination targets two separate mechanisms tumours use to avoid the immune system. Firstly, one drug (Ipilimumab) targets CTLA-4, which is made by the tumour to suppress the immune system. The second drug (nivolumab) targets a protein called PD-1, which prevents the immune system from killing the tumour cells, even if it does recognise them as bad.This is quite a significant breakthrough in the treatment of melanoma but it does come at a cost however. The treatment has significant side effects, with over 80% of patients experiencing these. Furthermore, 55% experienced severe side effects, and 36% of patients had to stop treatment as a result.There is also the issue of cost, a problem I have discussed in a previous blog. Ipilimumab has already been approved by NICE at a cost of at least £42,200 per QALY. Nivolumab hasn’t yet been appraised by NICE, so it’s cost per QALY isn’t available, but in the US it is slightly more expensive than Ipilmumab, costing roughly $150,000 dollars per patient per year. As a combination, it is estimated that it will cost patients in the US $295,000 per year. This may well prove a stumbling block for an already creaking NHS. However, as both Merck and Roche have their own versions of these drugs, the hope is that the competition will force the manufacturers to drop their prices. Whether they will or not remains to be seen.Unfortunately, this breakthrough isn’t the cure that some articles say it is. Between cost and side-effects, there will be problems prescribing it to many patients. It is a welcome advance however, and does herald the development of immunotherapy as another arm in our treatment of cancer.Edit (03/06/05): The $295,000 figure comes from adding the list price of the two drugs. Some outlets are reporting that a discount may be applied to that, making the drug considerably cheaper, potentially bringing it closer to $200,000 per patient per year. While this is a significant discount, $200,000 per patient per year is still a staggering cost. To put it in perspective, if every patient with late stage melanoma was given this drug, Bristol-Meyer Squibb would make over $2,000,000,000 per year from it. When you consider that this is from only the late stage patients, with only one type of cancer, you can see why some people have a problem with the pricing of this and other drugs.
