Biological therapy, biology, cancer, Explainer, genetic modification, Opinion piece, Radiotherapy, science fiction, science news

The future of cancer treatment, part 2

How often do you hear a new medical treatment, or any scientific or technological innovation, as “It sounds like something out of science fiction but WonderDrug X will cure Deadly Disease Y….” ? Too often, in my humble opinion, and, in my suspicions, by people who don’t read that much science fiction (or fact). But there are some cancer treatments coming up that have been mooted (or at least something similar has) in science fiction. Let me throw some catchphrases at you: “Personalised medicine”, “Biological therapy”, and, best of all, “Nanobots!!!” Which obviously deserve three exclamations all of their own. Amidst the headline tags, there’s a welter of confusing terms: “Targeted therapy”, “Immunotherapy”, “Oncolytic therapy,” “proton beam therapy,” and, my personal favourite, “Cyberknife”. Now I’ll go through some of the newer cancer treatments that come with these labels attached: some in use, some in development, and see if they do the justice hype – and if science fiction really did say it all first.

Nanobots

Nanoprobes_in_actionBorg nanoprobes, (Paramount pictures via Memory Alpha)

Let’s start with the most out-there sounding treatment first, because, interestingly, this is where a lot of science fiction has gone before: the idea of teeny-weeny (okay, to be precise, nanoscopic or at least microscopic machines) programmed to do all sorts of nifty things. Science fiction predicted these invisibly small machines long before we actually made them – and we are at least starting to make them. Arthur Clarke mentions them in a 1956 short story (The Next Tenants), which are microscopic, and they are also featured in stories in the late to mid 1960s by the likes of Stanislaw Lem and Robert Silverberg. Perhaps unsurprisingly, once the computer revolution of the 1980s was in full swing – and, it is worth noting, the molecular biology revolution kicks off – nanobots start turning from a niche idea into a trope of science fiction. Probably the most familiar of these are of course the cybernetic organisms the Borg from Star Trek, which also highlights an interesting trend in fiction: often this technology has negative consequences, usually because the nanomachines start reproducing uncontrollably, turning everything into a copy of themselves, and/or going beyond their programming in unforeseen ways. This is probably just for the purposes of drama, to be honest. The anime series Ghost in the Shell: Stand Alone Complex is noteworthy for using “micromachines” to treat complex diseases, including cancer, but these are also involved in making a person a cybernetic (mix of machine and human) organism.

Let’s be clear: nanobot therapy isn’t a treatment that is in use yet. But it is a treatment that is starting to enter trials. Another thing these nanobots aren’t, are little machines in the context of something mechanical, or even little computers. No Borg here yet. I find it fascinating that in fiction, nanobots are, generally, machines; electronic, mechanical, or electromechanical. This suggests to me a failure of imagination on the sense of scale: we tend to think of molecules as the materials, the building blocks of stuff, not machines – except biochemists and molecular biologists, who are used to regarding cellular components like enzymes as machinery. Molecules have mechanical properties, and they can do things as well as be things. One trial underway is constructing a DNA molecule that will fold up around a drug molecule, keeping it safely contained, like a basket, until it reaches the cancerous cell: binding to the cancer cell unfolds the DNA, releasing the drug. It sounds great but I can’t help but think an antibody could do it just as well: I imagine it depends a bit on what you’re using to target the cancer cell. I won’t delve into the details, there is a lovely summary here

Does anyone predict the use of engineered biological machines? I’m sure there’s more than one person, but the notable one I can think of is Greg Bear’s prescient 1985 novel Blood Music, which features genetically engineered white blood cells used to treat cancer. It’s notable for two reasons: the use of the body’s own cells as a biological weapon, and the use of genetic engineering, another science fiction concept that has traversed the credibility scale from outlandish to Happening Right Now. And yes, this is real treatment being trialled as we speak. Of course they haven’t started going off and manipulating matter at an atomic scale as Bear’s cells do (yet…) but these biological treatments are an exciting new field. Let’s look in more detail.

Targeted/biological therapies.

There’s a certain confusion of terms here, which is because they all tend to overlap, but it really doesn’t help the layperson get to grips with what the difference is. Essentially, targeted means that the treatment, whatever it is, is aimed more precisely at the tumour rather than a chemotherapy drug that goes throughout your whole body (“systemic”). I know. Does exactly what it says on the tin, etc. For example, you might tag these cancer cells using some sort of specific marker, and then use targeted therapies to focus radiation or inject drugs just into the tumour cells and not the healthy tissue around, or micro-inject a drug into the local blood supply of a tumour. On the latter note, which I won’t go into detail on, there are also angiogenesis inhibitors, which block the growth of blood vessels that supply tumours; these are in trials now.

One thing you might try to do is make the immune system recognise and attack the cancer cells. Ordinarily, your immune system makes antibodies to things it recognises as dangerous; these are just proteins that stick to bacteria or virus-infected cells. Either the proteins clog them up so much they mean the bacteria/infected cell can’t function, or they act as “red flags” that other immune cells (often ones called T-cells) recognise and can then destroy. You might artificially make an antibody that binds to something specific on the cancer cells and this primes the immune system to look for these cells and attack them. If this sounds like it counts as “biological therapy” or “immunotherapy”, that’s because it does. A lot of these things overlap, particularly if you’re trying to use a multi-pronged approach to kill the cancer.

One of the prominent recent successes has been targeting types of cancer that are hormone responsive. With breast cancer, what treatment is prescribed often depends on whether it is one of the cancers that is hormone-dependent or not (specifically “ER positive” or “PR positive”, i.e. if it is responsive to oestrogen or progesterone hormones), which is why some are suitable for treatment e.g. with momenta. The same applies for “HER-dependent” ones (human epidermal growth factor – as it suggests, a factor that encourages cells to divide). If the cancer is “HER2 positive”, there are monoclonal antibodies that can target this. There is also one drug that has the antibody with a chemotherapy drug attached to this which may be more effective but has more side-effects.

Biological therapies, to expand upon this, are a form of targeted therapy that uses the biological properties either of the cancer, or the immune system. Generally they either:

(1) Stimulate the immune system to help it recognise and kill cancer cells (immunotherapy).

(2) Use some sort of biological marker that the cancer cells possess to kill them. If you are using the marker as a “red flag” to alert the immune system, then that counts as a type of immunotherapy too. Quite often they are what is known as “monoclonal antibodies” – i.e. you make an antibody artificially yourself to attach to some marker it recognises on the cancer cells and then the immune system will destroy them.

A recent example of immunotherapy is Nivolumab. This is quite a clever system. I mentioned in part 1 that cells normally have a self-destruct programme that is supposed to activate in case the DNA is damaged and things go wrong (ideally preventing cancer). Many cancer cells have mutations that mean this doesn’t happen. Some types of cancer are even trickier though. The T-cells of your immune system have a signal receiving protein on their surface that can deactivate them – normally this is to stop the immune system overreacting and them killing healthy cells. Some cancer cells however also produce the signal that turns off the T-cells. Nivolumab is an antibody against this particular substance, which means that the T-cells can then be reactivated and attack the cancer. The data is quite promising, particularly in combination with another drug called ipililumab, which encourages the T-cells to multiply. The side-effects however can be fairly strong. There is actually a nice piece in the Guardian here that explains it quite well. I personally think this is a promising approach if it’s an appropriate type of treatment for the cancer in question, but this may be a bit of an unknown quantity as it’s very new. It has been used for metastatic melanoma, which is a tough one to treat, so that’s encouraging.
Oncolytic (viral) therapy.

Viruses normally infect cells, hijacking them and forcing the cells to make more copies of the virus. Usually the viruses then kill the cell as they burst out of it. The virus DNA also needs to be pasted into your cell’s DNA to make the cell machinery copy it. If you are using a virus to kill cancer cells, you genetically engineer it to infect only (or mostly) cancer cells and then simply let it kill them as the copied viruses burst out of the cells (this is what they call “oncolytic therapy”). Once the viruses have burst out of the killed cell, then they should go on to infect and kill more cancer cells. (Obviously you would use a type of virus that wasn’t going to make you really ill). Measles virus ones, for example, have mostly been used for bone marrow cancers – this is important, as measles viruses like infecting bone marrow cells. Some viruses naturally bind and disable a protein called p53, which is a major regulator of the cell’s death programme: the one that is supposed to activate and safely destroy a cell if something goes wrong with the cell cycle that controls when cells divide. If you engineer a virus that lacks the p53-binding protein, it will only be able to infect cancer cells that already lack the p53 gene, which is rather neat.

It is very nice in theory and looks impressive in lab results, but has had mixed results in clinical trials so far. Plus I personally would be leery of side effects. That measles virus trial for bone cancer had to use very high doses of virus, the side-effects of which were essentially that the body thought it was fighting off a measles infection. This is of course a general problem; viruses may be good at fooling cells, but the body is not defenceless and will mount an immune attack. The use of viruses for targeted therapies has been more miss than hit (failures include the delivery of the “correct” gene into the lungs of cystic fibrosis sufferers), but, in fairness, there has been concerted effort to iron out these difficulties, so it’s definitely in the “one to watch” category.
Fancy radiotherapy (as we biologists term it)

I think, on the science fiction side, that this can fall under the umbrella term of “Somebody points a fancy machine at someone that makes whoo-whooing sounds and cures them with a beam of light,” or variants thereof. See every version of Star Trek ever known. But radiation: it’s so science-fictiony isn’t it? All manner of sins can be excused with the euphemistic use of “particles” and “beams” and big shiny machines.

On the non-biological side of things, there are a number of treatments coming along that are essentially more refined/specialised/sophisticated versions of existing radiotherapy. Their main advantages are generally incremental improvements over more commonplace radiotherapy. Generally, you get more precisely targeted radiation, so you get less damage to healthy cells and less side-effects. The type of radiation used may be more effective at killing cell, and it is likely that the course of treatment will be shorter. Those sorts of things; improving or extending survival rates, and better quality of life, are particularly important when the treatment is essentially palliative. Different types are suitable for specific cancers, often in specific locations in the body. This includes proton beam therapy, which hit the news in the UK recently when some desperate parents took their child abroad for treatment, against the advice of their doctors. This uses protons – positively charged particles, which need to be generated using a particle accelerator. Which would be why it’s so hugely expensive.

Another example is the cyberknife. This should be a science fiction novel by Philip K Dick, it really should, but, alas, it’s not. It’s also not really the proper name: it is one of the proprietorial names for something called stereotactic radiosurgery (SRS: one or more stereotactic radiation treatments of the brain or spine) or stereotactic body radiation therapy (SBRT; within the body). This is basically using radiation therapy, but in a more precise way. They combine a robot-guided targeter with sophisticated ultrasound and/or CT scanning to pinpoint the tumour and only zap the cancer cells. You have to be able to see it on the scanners, and this usually means injecting the patient with something that will make the cancer cells light up. It is quite frequently used to get rid of e.g. secondary lung metastases that are pressing on airways, to alleviate symptoms like breathlessness.

Radiofrequency ablation is a slightly different approach, which uses targeted radio waves to generate heat in the cancer cells which kills them. It is used for early stage lung cancer and again for example to remove tumours pressing on airways, particularly if conventional surgery is not an option. It tends to work best for smaller tumours, and there aren’t many side-effects compared to some other treatments, but it is usually used in conjunction with other treatments. Given that it’s fairly straightforward with minimal side-effects, it may be worth it to improve quality of life, but in most cases it’s not going to be a cure.

Conclusion: does it sound like science fiction, because it is?

In a word: yes. One might easily argue that a great deal of our modern technology was once science fiction, but I think there is a noticeable trend in these ideas in fiction: they are initially mooted by one or two prophets, and seem pretty far out there: either the technological details are not gone into, or they’re guessed at and wrong. Once real science and technology starts offering up the possibility of these things however, they become more prevalent and more fleshed-out as concepts, and often more realistic. Then you almost get a switch back to science fiction jumping ahead: predicting new and more complex uses or implications of existing (or least partially developed) technology. As for cancer, it’s a process of attrition, but things are getting better all the time.

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