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?!

We need some CRE-ative solutions

“Superbug” is an expression we hear far too often. Due to our excessive use of antibiotics over the past 65 or so years we have excelled this term from a potentially comical image of a flying inset that fights crime, to something we genuinely need to fear in a medical context. Admittedly, I am not a fan of the term “superbug,” but it is certainly catchier than the more accurate description of drug resistant or multi-drug resistant bacteria. The bacteria that will most likely spring to mind as being “superbugs” are MRSA and C. difficile. Both of these bacteria are well known to plague hospitals worldwide and cause potentially life-threatening disease in those people at their most vulnerable (in hospital for some other aliment). While MRSA and C. diff. are well established as health care-associated resistant bacteria, a new player is starting to come to the attention of healthcare officials and its emergence is being greeted with genuine fear.

Before discussing these new resistant bacteria I’d first like to talk about why we have resistant bacteria at all. In one sense, we can blame evolution. Bacteria are always looking to survive and will evolve to deal with anything that threatens this. The emergence of resistance is a wonderful example of the process of natural selection that drives Darwinian evolution. Let us consider a situation in which a patient has a bacterial infection. If this patient takes antibiotics these will kill the bacteria and aid the patient’s recovery. However, not all bacteria are created equally and when they multiply the progeny can carry mutations that set them slightly apart from their parent. It is possible that these mutations confer the bacteria with a slightly increased chance of survival against the antibiotics. If this occurs then this, potentially lone, bacteria will survive at the expense of all the others and will continue to grow (‘survival of the fittest’). All the competition for space and recourses has been removed due to the death of all other bacteria so this resistant bacterium will thrive. In the face of continued antibiotic treatment any new mutations that confers even greater protection will cause the same affect, continually selecting the bacterium that has the best protection from the affects of the antibiotic. The logical end point for all of this is that a bacterium will emerge that is completely protected from an antibiotic and it will thrive and spread.

MRSA - probably the best known "superbug"

While it is easy to blame evolution for the emergence of resistant bacteria, that is not the full story; we as humans need to take a fair share of the blame. Since the discovery of a process for the mass production of penicillin shortly after the Second World War, we have overused antibiotics. Antibiotics have been overused in the context of bacterial infections and most likely have been used to treat bacteria that are not susceptible to that drug (only certain antibiotics are effective against certain bacteria). However, more worryingly there are many cases of antibiotics being used to treat infections not caused by bacteria, such as the common cold, which is ridiculous since the drugs only work on bacteria (like using a cough sweet to treat a heart problem). The reason that overuse, and incorrect use, causes an issue is that we have billions of bacteria inside us; put these in an antibiotic context and you promote the emergence of resistance. Consider the fact that MRSA is a strain of the bacteria Staphylococcus aureus, a bacterial species that the vast majority of us have naturally in our lungs and on our skin, the only difference is MRSA has evolved resistance to the antibiotic methicillin.

MRSA and other resistant strains of bacteria are dangerous, however we do still have some “last line of defence” antibiotics that can be pulled out at the last minute to save the day like a cheesy action film. However, more and more cases of a new type of resistance are being seen, particularly in the USA, known as CRE. CRE stands for carbapenem resistant Enterobacteriaceae, with carbapenem being one of our few remaining “last line” antibiotics. Enterobacteriaceae are a bacterial family that include many well-known bacteria such as E. coli, Salmonella, Shigella and Y. pestis (which caused the Plague).  These are the well-known species in the Enterobacteriaceae family; however so far, most cases of CRE have been seen in Klebsiella and Enterobacter species that cause lung, intestinal and urinary tract diseases.

CRE bacteria have been spreading through the USA since their first detection about 5 years ago. Studies have suggested that these bacteria are endemic in major population centres such as New York, LA and Chicago (a report suggests that 3% of patients in intensive care units in Chicago carry CRE bacteria). There are also small pockets of CRE throughout other areas of the USA. So far CRE cases have been confined to health care facilities such as hospitals and care homes, as is the case with other “superbugs” such as MRSA. However, as with anything there is always the potential for spread outside of these facilities. The thought of spread is a worrying one when you consider the fact that CRE infections currently carry a reported 40% mortality rate, much higher than that of MRSA. If I was writing this blog for a newspaper this is where I would leave that statistic, 40% of people who get CRE die, everyone be scared and fearful! However, mortality rates are a pretty useless statistic as they rely on the ability to detect every single case of CRE to be accurate, yet chances are, only the most serious (and therefore life-threatening) cases are likely to be detected, skewing the data in favour of a higher death rate. When you also consider that until recently CRE has not garnered much attention, meaning no-one has really been looking for it, you get a further skewing of the data (only the most serious will be taken notice of). There is also difficulty in detecting CRE bacteria since carbapenems are not readily used, in the hope of preventing the emergence of resistance. This is not to say we shouldn’t consider these bacteria as inconsequential and we should (as we are) be treating them with a well-deserved level of respect.

The bottom line is that CRE bacteria are resistant to our last remaining antibiotic against this family of bacteria. All that we can do at this stage is prevent, the age-old techniques of rigorous hand washing, protective clothing and isolation are the main ways to protect from CRE infection. If someone becomes infected there is no effective treatment, with the exception of some old antibiotics that have been shelved for years due to their high toxicity (not necessarily something you’d want to take).

CRE bacteria are something we should be rightly fearful of, however they also bring to the forefront a gapping hole in our medical research. While we have some new and improved antibiotics in the pipeline, very few of these are though to be of any use against CRE, and there is very little incentive for the major drug companies to look for ways to tackle CRE. The problem lies in the fact that antibiotics just don’t make enough money. Why would a major drug company want to spend a fortunate making a drug that is used for maybe a couple of weeks, until the patient recovers, when they could spend their money making drugs to target chronic diseases that will need to be taken for the rest of a patients life. Not only is the treatment time short, but also resistance emerges so quickly that any drug produced could rapidly become obsolete, making the money spent useless. It sounds wrong to neglect people who could die from an infection on the basis of economics, but unfortunately, that is how it is, in the bluntest (and a slightly cynical) way.

I titled this blog post as the fact that we need some creative solutions, both for the play on the CRE bacteria naming and because, simply put, we do. There are ideas out there, such as the use of phage to kill bacteria. Phage are viruses that only infect bacteria so if we can find a way to use these then it may provided a good alternative to antibiotics. There is also work being conducted to look for new and untapped sources of antibiotics with the discovery of new fungi and bacteria (which produce antibiotics) in obscure locations such as caves and oceans, however, as I’ve alluded to, there is a shortage of funding in these area.

Process of conjugation, one of the main ways resistance spreads

One potentially promising area of research may lie in targeting the mechanism used by bacteria to spread resistance. Resistance is controlled by the production of protective proteins from genes. It is very common that these genes are located on mobile genetic element known as a plasmid (stick with it as I will clarify what that means). Like us, bacteria have a genome that contains all the instructions needed to produce a functional bacterial cell. However, in addition to the genome many bacteria can have addition chunks of DNA (plasmids). These extra units of DNA float around the cell, separate from the rest of the genome, and can be passed from one bacterium to another. Think of this like books, if the genome is a full instruction book for producing the bacteria then a plasmid, is like a page taken from another book. These plasmids (extra pages) can move between bacteria through a structure known as a pilus, in a process often termed bacterial sex (due to some obvious similarities – Google it). If we can find ways to block this process, correctly known as conjugation, then we may be able to stop the spread of genes that confer resistance and maintain the efficacy of our current stock of antibiotics. However, as it stands, this is just a hypothesis.

CRE bacteria are worrisome, they are resistant to pretty much all of our current stock of antibiotics and the number of cases are on the up. There is a reported death rate of around 40% for CRE infection, and while this may be slightly skewed, it is still clearly a dangerous situation we find ourselves in. We need new and innovative ways to tackle these bacteria as simply stopping the spread with preventative measures can only go so far. However, whether the funding will reach the research into these areas is yet to be seen.