Thursday, 10 January 2013

Are we on the road to curing leukaemia? With HIV!?

Imagine having leukaemia. A cancer of white blood cells, the same white blood cells that usually fight off invading organisms and help keep you alive, but cells that are now slowly killing you. After numerous rounds of chemotherapy nothing has helped and you’re knocking on death’s door. At this point would you allow doctors to remove close to a billion of your cells and infect them with HIV in an attempt to cure you? Sounds strange and counter-intuitive, but this is exactly what is going on in Philadelphia, and even more strangely it is saving lives.
A white blood cell amongst red blood cells

So far results have been released for a dozen patients that have received this very treatment for advanced chronic leukaemia. Out of these twelve, three adults and a child have gone into complete remission and four additional adults have significantly improved, although have not entered remission (the rest showed no effect). So what is this magic HIV that is helping ‘cure’ people of leukaemia?

HIV is a retrovirus that integrates its genome into our own; tricking our cells into producing the viral proteins needed to spread HIV (the virus cannot produce these itself). Since HIV can add DNA to cells and cause new proteins to be expressed it has always been hoped that we may be able subvert this system and use it to our advantage. What is to stop us using HIV to deliver genes into cells to produce helpful and useful proteins? Imagine a patient has a disease because they are missing a specific protein, why can we not use HIV to infect the cells and produce the protein, and thus cure the disease? The answer is that we can do this. However, the issue is safety and actually getting it to work in a human being, not just cells in a lab, many trials for genetic engineering have caused cancers or simply not worked. Excitingly, these two hurdles have, for the most part, been cleared for leukaemia treatment.

Leukaemia cells
In the trials being conducted in Philadelphia HIV is being used to carry a gene into T cells (a subset of the white blood cells that make up our immune system) that allows them to detect and kill leukaemia cells. I have been saying that they use HIV, however this is not strictly true as the virus has been “gutted,” it is just the bare bones of a HIV virus (like stripping a car down to the chassis). All of the genes that would normally allow the virus to spread from a cell it infects have been removed, meaning the virus is only able to enter cells, produce DNA for the gene and then insert it into the genome (it is a dead-end infection since cannot spread from integration). The gene carried by this specially modified HIV allows the T cells to recognise a protein known as CD19. Whenever a T cell binds to this molecule on another cell’s surface it will kill this cell, the CD19 is a big bull’s-eye for the modified T cells (like a hunter tracking a deer, only when he sees the deer will he shoot and kill it). CD19 is a protein expressed exclusively on B cells, another subset of our immune system cells. These B cells are the very cells that mutate and become cancerous in leukaemia patients. By using HIV to genetically engineer T cells we are able to produce an army of leukaemia killing cells.

So how does this all work in reality? So far the trial has been conducted on patients who are at the worst stage of their disease, they have had multiple rounds of chemotherapy and still the cancer persists. The only remaining option would be a bone marrow transplant, a risky and costly procedure. Instead, the patients in the trial have their blood filtered to remove as many T cells as possible. This allows the scientists to collect roughly one billion T cells from the patient. These cells are then treated with the specially modified virus described above making them able to target and kill cells that carry the CD19 marker. The genetically modified T cells are then frozen and stored while the patient receives another round of chemotherapy. This chemotherapy kills all of the T cells in the patient’s body that escaped the filtration process so that they won’t interfere with the genetically engineered cells. Once this has been done, the genetically modified T cells are thawed and infused back to the patient’s blood from where they set out on their mission to kill all the cancerous cells they can find.

It’s tempting to jump to the conclusion that we have cured leukaemia, but lets not speak too soon. So far, only a very limited number of patients have received this treatment, many more will need to be tested before we can begin to talk about a cure, however, it is a very promising step in the right direction.

There is a big but to this tale, in that there are severe side effects. When a patient first receives the infusion of their cancer fighting army they enter a state medics nickname ‘shake and bake’ due to patients entering a horrible period of fever and chills (chills causing shivering/shaking). The more technical description for this is a cytokine storm. Cytokines are proteins released by immune cells when they are fighting and killing something, such as cancer cells, or more commonly invaders such as bacteria or viruses. It is these cytokines that are responsible for fever and other general symptoms you get when you are ill (‘shake and bake’ is just an exacerbation of this normal response). The storm can be so strong that drugs may be needed that mop up some of the cytokines in order to save the patient’s life, as was the case with a 6 year old child who receive the treatment (she went into full remission though so it ended well).

A second side affect is known as tumour lysis syndrome. When cancerous cells are killed they release a lot of chemicals, when a lot of cells are killed, a lot of chemicals are released. All of these chemicals need to be filtered out of the blood in the kidneys. When there are excessive levels of these chemicals the kidneys can become clogged up and damaged. So kidney damage is a potential side effect of the treatment, indeed one patient had to take drugs to prevent this from happening.

Injectable antibodies
The final side effect to consider is that the cells don’t discriminate between cancerous B cells carrying the CD19 protein and normal, useful B cells that also carry it. Therefore these engineered T cells don’t just target cancer, they go on a murderous rampage and kill all B cells in the blood, cancerous or otherwise. Unfortunately, B cells are pretty damn useful because they produce antibodies that help protect use from invading organisms such as bacteria and viruses. Fortunately there is a way around this through the intravenous administration of antibodies (a fancy way to say we can inject antibodies into a patient to protect them) once every couple of months. Unfortunately, in a sense, these antibody injections need to be taken for the rest of a patients life because the T cells persist in the body as memory cells (just like normal T cells) However, while this persistence means life long injections it does mean that should any cancerous cells start to emerge they will be killed straight away, so it’s probably worth it.

There are side affects and risks associated with this treatment, but would you rather go through a short period of fever, chills and the risk of kidney damage followed by life-long injections of antibodies or die of leukaemia? A bit of a no brainer really.

As I’ve said it’s still early days for this treatment, however that hasn’t stopped Novartis, a major global drug company, noticing the promising work and committing $20 million to a new research centre at the University of Pennsylvania in order to bring the treatment to market. As things stand the treatment costs in the region of $20,000 per patient, which isn’t exactly cheap (albeit cheaper than a bone marrow transplant). However with the funding from Novartis, and continued work in the field this figure is likely to drop. It may not be long before we start winning our war against leukaemia by turning our usual adversary HIV into a friend. Even more exciting is the fact that this approach could potentially be modified to target other forms of cancer, could HIV be our cure to cancer?!

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