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.
Vaccinating ourselves against cancer
Several news outlets carried a story this week regarding very promising results of cancer vaccines trials. This was a very small trial (on just three patients) who had an aggressive and late-stage skin cancer known as melanoma. In all three patients the cancers stopped growing, and they were alive and well at the time of publication. In spite of the low number of patients, this study provides a tantalising glimpse of a brand new form of cancer therapy.
So how would these vaccines work? The aim is to teach the patient’s own immune system that cancer cells are bad. That way, our own bodies could potentially mount a natural and effective response, free of the side-effects of conventional chemotherapy. Myriam has previously posted a great blog on how the immune system works (which can be found here), so I’ll stick to the basics.Our immune system recognises invaders or abnormal growths by reading what molecules are sticking out from the surface of cells. These molecules are known as antigens. If the immune system recognizes a cell's antigens as being foreign or abnormal, it will mount an immune-response to clear it from our system. The key is to correctly differentiate foreign antigens from normal, and this is the responsibility of a group of “teacher” immune cells which differentiate friend from foe and teach the other immune cells to do the same. These teacher cells include cells known as “dendritic cells”, which were used in this study.However, cancer cells are problematic for these “teacher” cells. Because cancers arise from a cell that was once healthy, they are sometimes not recognised as being abnormal, and as a result the immune system isn’t alerted to the problem.What these scientists did was to analyse the cells in a biopsy of the patient’s tumour to understand what molecules (antigens) are sticking out from the surface of only the cancer cells. The next step was to train the teaching cells (dendritic cells) to see these specific antigens as foreign. These newly-educated dendritic cells were then put back into the patient’s blood, where they could teach other immune cells to attack the tumour. Encouragingly, after the dendritic cells were infused back into the patients, they mounted a massive immune response to the tumour. It remains to be seen whether this presents a long term solution to these people’s cancers, but it is an exciting “proof of principle” study.This is a very promising new therapy for cancer. It has the potential to be very specific to the tumour and hence have very few side effects. Large scale use of such technology is still quite a few years away, but his is a very exciting step along that path.
