Blood, of course, plays a crucial role in keeping our bodies alive and functioning.
Red blood cells carry oxygen from our lungs to our muscles. White blood cells are the first responders of our immune systems, detecting infections and foreign agents and triggering the immune response needed to deal with the problem. Plasma, the liquid part of blood, transports not only the cells but also proteins, such as antibodies, and hormones, such as insulin, to every part of the body. It is a beautifully complex system that is the key to our bodies’ functioning correctly.
Parasites, viruses and bacteria all use the circulatory system to spread around the body. When cancer metastasises and spreads to other parts of the body, it is through tumour cells circulating within the bloodstream. There are also myriad blood cancers, such as leukaemias and lymphomas, and blood disorders, such as sickle cell anaemia, not to mention autoimmune diseases like diabetes or lupus. Sepsis, also known as blood poisoning, is a deadly overreaction to an infection which also has its roots in blood.
Magnetic blood filtration is a tool which enables the physical removal of specific substances from the bloodstream
Most of these diseases are treated with drugs or chemotherapies, some with great success, others, much less. There are also various methods of physically extracting different components from the blood by circulating a patient’s blood outside of the body through what’s known as an extracorporeal circuit. Dialysis, for example, removes excess toxins from the blood, acting as a substitute for kidneys when they fail. Plasmapheresis and leukapheresis are methods of removing harmful antibodies from the plasma or white blood cells from the blood. Similar techniques are also used to harvest stem cells from the blood, which can then be used in cancer therapies (known as stem cell transplantation), if the donor and patient are a match.?
Magnetic blood filtration
Despite these methods, millions of people still die every year from blood-borne diseases. At MediSieve – a small, London-based start-up company – we are using nanotechnology to develop a new technology which we think can transform our ability to tackle these conditions.
Magnetic blood filtration (MBF) is a tool which enables the physical removal of specific substances from the bloodstream. It is similar to other extracorporeal procedures like dialysis, but instead of removing every component of a particular size or weight, MBF removes highly specific targets to address the specific medical issue, thereby removing only the substance that doctors want to remove. Alongside this high specificity, various targets, both big and small, can be removed simultaneously, raising the prospect of removing for example specific cells and harmful antibodies in a single procedure.
To achieve this, we use magnetic nanoparticles coated with binding moieties, such as antibodies, which bind specifically to the desired targets in the blood. These particles are infused into the blood within the extracorporeal circuit, binding to their targets. The blood then flows through a magnetic filter which captures the magnetic particles and the targets bound to them, while the rest of the blood flows back into the patient. Several different particles can be used in the same procedure in order to capture different components. Using this method, anything for which there is a specific antibody or other binding moiety can theoretically be removed directly from the bloodstream. I think that in the long-term the technology could be used to remove specific cells, antibodies, bacteria, viruses, toxins, drug molecules and inflammatory cytokines, the drivers of immune conditions such as sepsis.
The MediSieve Filter is a disposable, single-use device in which the magnetic particles and their targets are captured. It is inserted into the MediSieve Magnet, a reusable medical device which “activates” the filter. Both can be incorporated into a variety of existing extracorporeal systems and integrate with standard blood pumps and tubing sets.
We are currently developing treatments for malaria, sepsis and leukaemia. The Filter and Magnet have completed pre-clinical testing and are now ready for clinical trials, which we hope to start shortly. Magnetic particles for various clinical targets are currently being developed and validated in the laboratory, with promising results. Animal trials for these are expected to start in 2020.
Our potential treatment for malaria is the closest to market because malaria infected cells, uniquely, have naturally occurring magnetic properties – is it therefore possible to remove them from the blood using the MediSieve Filter without the infusion of any magnetic particles. The magnetic properties arise from a core aspect of the malaria parasite’s lifecycle. After infecting a red blood cell, the parasite consumes the protein part of haemoglobin, leaving behind an iron-based waste-product known as haemozoin, which is stored inside the cell. Haemozoin is paramagnetic, thereby giving infected cells their unique magnetic properties.
MBF could be used in highly severe malaria cases in which the patient is hospitalised and at high risk of death. Currently, these patients receive intravenous drugs such as artesunate which can achieve parasite clearance in 36-48 hours; parasite clearance rate is the key indicator of patient recovery, and it can take up to eight doses of IV drugs to achieve complete clearance. Mortality in these cases can be as high as 20%.?
Using MBF alongside the first dose of IV drugs could drastically accelerate parasite clearance rate. We claim that, depending on the patient size and initial level of infection, this approach can remove over 90% of red blood cells containing haemozoin in just two hours. Because they have higher quantities of haemozoin, MBF is better at removing later stage infected cells, whereas drugs are much more effective against earlier stage cells, so they should be complimentary.
MBF has the additional benefit of removing free circulating haemozoin, also known as the “malaria toxin”, which should also improve the treatment for the patient since drugs can cause the large-scale release of haemozoin as infected cells die.
According to the WHO, in 2017 there were 219 million cases of malaria and 435,000 deaths, mostly children. While overall malaria cases and deaths have been trending downwards in recent years, the number of hospitalised patients is increasing as healthcare infrastructure improves in malaria endemic countries and more patients gain access to hospitals. In the future, MBF could be adapted for use in mobile clinics to reach harder to access areas.
While ourinitial target is severe malaria patients, I also believe MBF could be a valuable tool in the fight against drug-resistant malaria strains, which have been emerging in SE Asia and are causing great concern – if drug resistance spreads to Africa, the effect could be catastrophic. It can also be used to treat patients for whom drugs cannot be used, such as pregnant women.
Sepsis is one of the leading causes of death in the developed world with more than 1.9M cases in Europe and the US and published mortality rates of 29% - 50%. Sepsis is a complex syndrome in which bacteria or other pathogens create a dysregulated immune response which can escalate to organ failure and death. The immune response creates an overproduction of pro-inflammatory cytokines, while cell damage over time creates damage-associated molecular patterns (DAMPs) that sustain the syndrome. ?
Our approach to sepsis, which we call SepSieve, uses a cocktail of different particles to remove a number of targets from a patient’s bloodstream: specific pro-inflammatory cytokines (IL-1β, IL-6 and IL-18), DAMPs (HMGB-1), endotoxins (LPS), and gram-negative bacteria. This multi-modal approach tackles the disease from two key angles: Removing the pathogens and endotoxins that trigger the immune response and reducing magnitude of the immune response and preventing the “cascade” towards septic shock.
Like in malaria, SepSieve would be used alongside existing frontline treatments, specifically antibiotics. While antibiotics are critical for treatment of sepsis, the bacterial cell death they cause releases LPS which accelerates the dysregulated immune response – MBF could remove the LPS to prevent the condition from worsening. The main benefit of MBF in sepsis is therefore not so-much the removal of bacteria itself (which is tackled by antibiotics and in any case is not present exclusively in the bloodstream), but rather the removal of all the other components driving the disease.
Gram-negative bacteria such as E. coli account for approximately 50% of sepsis patients, but thanks to the removal of other substances, particularly HMGB-1 and the inflammatory cytokines, I think the combined approach could benefit all sepsis patients. Since magnetic filtration is a purely physical method, it can also target and remove pathogens which are resistant to antibiotics, which again are a huge concern with increasing occurrences of resistant infections in hospitals.
Like in malaria, wwe plan to apply sepsis treatment to hospitalised patients and specifically those in Intensive Care Units. These are the most severe cases and those who stand to benefit the most from the treatment. The idea is to intervene early to prevent the “sepsis cascade”, in which the disease escalates eventually causing organ failure and death.
In fact, we managed to secure grants worth a total of £1.56M from Innovate UK, the UK’s government grant funding body, and the UK National Institute of Health Research to develop and validate our sepsis particles. Currently being tested in human blood models in the company’s laboratories, we plan to start animal trials in 2020 which, if successful, will be followed by clinical trials in 2021.
One of the advantages of the particles we develop to remove pro-inflammatory cytokines for sepsis is that they can also be used in other diseases. This includes auto-immune diseases and cytokine storms such as cytokine release syndrome (CRS), a common side-effect of newer leukaemia treatments known as CAR T-cell therapies.?
In CAR-T therapies, T-cells, a type of white blood cell, are modified to attack cancer cells in a patient’s bone marrow. Taken either directly from the patient or from a matching donor, the modified cells are infused into the patient in order to directly attack the cancer. Results of clinical trials have been mixed, but these cell therapies are seen as a huge leap forward for leukaemia treatment.?
The problem is that the infused T-cells trigger massive immune reactions within the patient. Indeed, that is the intention – the immune reaction is intended to kill the cancer cells – but it can easily escalate into the condition called CRS. The result is similar to sepsis – an immune over-reaction which attacks the patient and can be fatal. Immune mediators can be used to calm this reaction, but they then prevent the infused CAR-T cells from having their effect, eliminating the therapeutic benefit of the treatment.
Our proposal is to use MBF in CRS patients to remove cytokines from the bloodstream. This should calm the immune reaction, alleviating patient suffering and eliminating the risk of death. But since MBF only removes cytokines from the bloodstream, it shouldn’t affect the immune effect of the CAR-T cells in the bone marrow, so the therapeutic benefit should be maintained. In addition, MBF can be stopped at will, so it can be used to “control” the immune response by maintaining the correct balance of cytokines – this is of course not possible with immune mediators which are infused into the patient.
A further benefit that MBF can provide in leukaemia patients is the removal of leukaemia cells from the bloodstream – leukaemia patients commonly have very high white blood cell counts due to circulating leukaemia cells. These cause a number of issues such as a reduction in immune function, making patients more vulnerable to infection. They can also prevent certain chemotherapies from working effectively, since they “block” the drug from targeting cancer cells in the bone marrow. High white blood cell counts also increase the risk of side-effects during treatment, since the sudden death of such a large numbers of cells causes debris to circulate in the blood, putting strain on the body and causing immune reactions like CRS; this is known as Tumour Lysis Syndrome. ?
We are currently focussing development on their sepsis particles, but plan to trial their cytokine particles in CRS at the same time as they are trialled in sepsis, since the pre-clinical validation for each disease is the same. The particles to remove white blood cells, however, are at an earlier stage and will be developed further down the line.
Our ambitions for MBF are certainly large. In the long-term we want to revolutionise the way in which blood-borne diseases are treated. Going far beyond malaria, sepsis and leukaemia, we want to develop treatments for all blood-borne diseases – if it’s in the blood, and doctors want it out, we want to be able to take it out.
My vision is that hospitals all around the world will have “Magnetic Blood Filtration Units” which will address a huge variety of patients. Only time will tell if this can be achieved, or even if our technology will work at all – after all, there have, as of yet, been no clinical trials.
However, the ability to remove specific substances from blood would clearly be of benefit to huge numbers of patients. It is something that we cannot do today, but we certainly should want to be able to do tomorrow. Whether it is MediSieve who gets us there or not remains to be seen.
Dr George Frodsham is CEO and founder of MediSieve