Immunotherapy - Switching Anti-Cancer Immunity Back On

The immune system is a powerful tool that protects us from being infected by the many bacteria, fungi and viruses that would otherwise find a warm wet nutrient rich wound an ideal place to colonise. But it also has a role in protecting us from our own cells. Immune surveillance is the body's way of keeping a check on cells that begin to divide uncontrollably. Such cells have mutated somehow and will be recognised as defective and destroyed by the immune system. Generally this works very well for most of our lives; unfortunately it applies the 'survival of the fittest' rule to cancer cells. The 'fittest' cancer cells being those that acquire the mutations enabling them to mutate faster than the immune system can recognise them, or those that acquire a mutation that causes some kind of immunosupression. Eventually the cancer evolves to a form that completely evades the immune system, usually by secreting a cocktail of chemical messengers that stop immune cells recognising them.

Many approaches are being tried in an effort to make the immune system recognise the cancer again and begin killing it. Cocktails of lab-grown tumor cell vaccines have had mixed success in trials, ongoing are Phase II trials by Onyvax whose therapy consists of three types of lab grown cancer cells, which are injected into patients with prostate cancer. The immune system will recognise these cells as totally foreign, and in the process should notice some cancer associated proteins which it had previously missed due to the immunosuppression by the cancer. Although this approach has shown some effectiveness in previous trials by extending patients lives by around 6 months, it only slows the cancer and never causes remission. This could be because this approach doesn't do anything to overcome the immune suppression by the cancer, there may very well be a well armed immune response ready to attack the cancer, but every time it gets close it is prevented from attacking.

Dendreon is another company with a prostate immunotherapy, this one uses lab-primed immune cells called Antigen Presenting Cells (APC) and injects them into patients, once in the patient the APCs 'teach' the patients immune system to attack the cancer. This approach is similar to the Onyvax approach, but is further in development, unusually it is in its 3rd Phase III clinical trial, ideally those should only happen once. It is clearly having an interesting effect on cancer, enough to continue investigations, but its not significant enough to bring it to market yet. Again, this therapy doesn't address the issue of immune suppression.

Cell Genesys had a vaccine very similar to Onyvax's, except it included an extra immune stimulatory factor in an attempt to overcome the immunosuppression with an even more powerful immune response. This attempt failed, their PhaseIII trial was terminated and the therapy abandoned. Things are beginning to look a bit bleak, I shall bring us onto some more promising therapies.

NovaRX have a therapy similar to that of Onyvax and Cell Genesys but for advanced lung cancer, it uses four sorts of cancer cell in its vaccine; crucially it also blocks a signal protein called TGF-β, which is an immunosuppressor secreted by the tumor cell. This approach seems to be highly effective, extending patients lives by years in a phase II study and is now in a PhaseIII study.

These types of therapies are important, because once a working therapy is produced for one cancer type, the same approach can be used for nearly all other types of cancer. In all of these trials however, the vaccines usually only work for a certain subpopulation of those tested. I wrote previously about the great variation in cancer between people and the need to personalise treatments using biomarkers. These companies will be monitoring patients and discovering biomarkers that will help optimise future treatments with their products.

One way to overcome the problem of treating unique cancers with general vaccines, is to make the vaccine unique to the patient. Antigenics have a vaccine which is tailored to each patient by taking a biopsy of the tumor, taking it to the lab and creating a personalised vaccine from it. This vaccine has been effective in prolonging survival in kidney cancer and melanoma has been approved for treating kidney cancer in Russia and has been submitted for approval in Europe.

I have presented a small selection of therapies here, a search of 'cancer vaccine' on clinicaltrials.gov provides a list of 303 clinical studies that are seeking patients, hundreds more have completed recruitment and are ongoing. So there is much more information to be gained in the not too distant future. Using this information the next generation of cancer vaccines are likely to incorporate several modes of action including blocking the immunosuppressive activity of the tumor, priming the immune system to attack, and boosting that attack with immunostimulators. Perhaps by doing this, we will be able to extend lives by decades rather than months and years.

Targeting Therapies

Getting your drug therapy to the tissue that you want to treat is easy, the body's circulatory system is perfect for that. The problem occurs when the drug gets into other tissues and causes side effects, a long list of which can be found on the information sheet supplied with any drug.

There are a multitude of different ways of specifically targeting certain tissues or cells, and many new ways being developed with the use of new nanotechnology. One such method is being developed at the City University of New York. Here the drug is attached to a mesh of fatty acids, making it inactive. This mesh will disperse around the whole body like any other drug, but could be designed so that the drug can be detached from the mesh by an enzyme that is only present in the tissue being targeted. In this way the drug is only released in its active form at the desired location, thus limiting the chances of the drug getting into other tissues and causing side effects. This is in very early development and has yet to be proven outside of bench-top experiments, there is undoubtedly still a lot of work to be done to make this method work, but it shows us the kind of thinking going on in this area at the moment.

Here's some background to a different problem. DNA encodes the 'blueprints' for all the proteins your cells need to do their business, it is like the master copy. When the cell needs to make a protein it uses a slightly different chemical called RNA to make a copy of the gene, the cell then uses that copy to construct the protein. Many copies are made and transmit the message of how to construct the protein to the cellular machinery. When a cell is making a protein that it isn't supposed to, it can often cause disease. In the lab it is possible to block the RNA message by designing small segments of interfering RNA that stick to the RNA message. As the cellular machinery works its way along the message, making the protein as it goes, it reaches this interfering RNA segment and can't read the message anymore because it is blocked out and so the protein is never completed. Inject this interfering RNA into the body however, and you'll find it is destroyed pretty quickly in the blood before it ever reaches where it supposed to.

Calando Pharmaceuticals in California are testing in humans a kind of Trojan-horse system where the interfering RNA is packaged inside a nanoparticle studded with a molecule called transferrin. They chose this molecule because cancer cells are abnormally rich in receptors for that molecule, and when they detect it on the particle they will take the whole particle inside the cell. The acidity inside the cell is different to the blood, and this causes the particle to burst, releasing the interfering RNA into the cell where it can do its job. This technique is very promising as it can relatively easily be modified to target any receptors and deliver interfering RNA to all sorts of cells, not just cancer cells, and could potentially be adapted to deliver regular drugs.

A third approach is to make the cells produce the drug themselves. Viruses exist by infecting cells and making them produce all the proteins it needs, the virus just brings along the appropriate genes and the cell does all the work. Viruses are also very specific about the cells they infect, which is half the work already done for us. They are already being used selectively infect cancer cells, thereby killing them. Companies such as Oncolytics, Genelux and others are carrying out trials of this method. Viruses or artificial virus-like particles can be designed to deliver a gene for a specific enzyme that makes an active drug out of an inactive 'pro-drug' that is injected normally. This means the infected cell becomes a kind of drug factory at the precise location the drug is required, minimising the exposure of the rest of the body to that drug.

In ways such as these the treatments of the future will have a much reduced range of side effects, while at the same time being more effective and improving the quality of life of people suffering from chronic diseases.

A Little Help from Man's Best Friend

My last post suggested that some new drugs don't make it to market because the existing trials process doesn't provide critical information that can be used to optimise the trial design and reveal the true potential of the drugs being tested.

A change in the existing trial process would have serious legal and ethical issues to contend with, and so is unlikely to occur. It can however be supplemented in such a way that streamlines the process, more accurately determines the effect of a cancer drug and can reduce the time to market. That solution is dogs. These are not your typical animal experiments, such as the rat or mouse models of cancer, in which the animal often lacks a fully functional immune system and the cancer itself is a cross-species 'xenograft' implant. Its fairly easy to see how these models do not accurately represent the type of cancer that occurs naturally in the body, and that's where the dogs come in.

In the USA up to 6 million pet dogs are diagnosed with cancer every year. Canine cancer is surprisingly similar to human cancer. Dogs get the same types of cancers as humans, they are genetically similar to humans and crucially, large scale genomic analyses of canine tumors have shown that there are no differences in the genetic mechanisms of the cancer. The other similarities in canines include their size and the fact that they possess fully functioning immune systems. The similarity between dogs and humans is so close that most existing drugs can be used to treat equivalent diseases in both species.

Naturally dog owners are keen to pursue any therapies that may prevent the death of their pet. Fortunately they can, in the USA the National Cancer Institute operates a network of animal hospitals, fully equipped with state of the art imaging technologies to accurately diagnose and monitor canine cancer. Similar work is carried out at the Roslin Institute in Scotland. These centres are used to test new therapies on the plentiful supply of canine patients following Good Clinical Practice guidelines and central reporting of dangerous side effects not too dissimilar to those in place to protect human patients.

The canine trials can start providing detailed information on the mechanisms of the drugs action before even the Phase I trial in humans starts. Information such as genetic profiles for which the drug is ineffective or blood markers that can be used to determine successful responses in advance of significant tumor reduction. These can all be translated to human systems and used to better design the human trials. These types of biomarkers are not often discovered until around Phase II of human trials, and are usually validated during phase III. Having them in place for Phase I is very useful as they can be validated in the early phases and used to optimise the later more expensive and time consuming phases. For example selective enrolment of patients who have the genetic or biochemical profile compatible with the drug would make the trial more decisive, while freeing other patients to pursue other therapies with more likelihood of success for them. Another benefit is instead of waiting years to determine the survival of the patient and therefore whether the drug was effective, biomarkers that provide advanced indicators of survival could provide that information in months, drastically reducing the length of the trial and therefore the costs.

Comparative Oncology such as this has the potential to give us a much more detailed understanding of the drugs we are testing and should help bring more new drugs to market and quicker. Cancer is a complex and diverse disease that will not be overcome by a single therapy alone, we will need to use combinations of therapies specifically targetted to a patients personal disease to attack it from several fronts. Therefore understanding each cancer type and each drug as much as is technically possible will be critical in determining potential drug synergies and creating successful recipes for treatment.

The Problem with Clinical Trials

All new medicines undergo a rigorous series of controlled studies to establish safety and efficacy before they are licensed. The need to test drug safety on a small scale before allowing it to be prescribed was underlined in the early 1960's by the well known Thalidomide Tragedy, a situation where the drug thalidomide was prescribed to pregnant women in Europe and Canada as a treatment for morning sickness. Unfortunately the drug had only been tested in animals, and nobody foresaw the severe birth defects that would be inflicted on the children of these women. In 1962 the US Food and Drug Administration (FDA) put a system in place to ensure all new drugs would be rigorously tested before coming to market.

This has resulted in the clinical trial system we have today which typically consists of three phases. Phase I begins if laboratory and animal experiments have shown convincing evidence that a new drug is effective and safe. At this stage the primary concern is drug safety and only the minimum number of patients will be treated, initially with a very low dose of the drug, increasing gradually as the trial proceeds. If the trial goes well and no patients were harmed by the drug, then it may enter phase II. In Phase II the objective is often to establish an effective treatment regime, different dose levels and frequencies are likely to be tried in order to establish how to make the drug most effective. At completion of this phase the data will be studied to determine if there is a benefit associated with use of the drug. If there is, then phaseIII will begin, often with hundreds of patients in a large scale placebo controlled study across many sites to establish beyond doubt whether the drug is truly beneficial.

The problem with this system is that it is very expensive and is a very long process, taking up to a decade or more to complete. The race to get the drug to market means companies often try to complete the first two phases as soon as possible, they see promising data from these trials and dive headfirst into PhaseIII to save as much time and money as possible. This means that detailed studies into the method of action of the drug are often overlooked, as it isn't considered worth spending the money on that until you know the drug is safe and effective, its as if nobody cares how the drug works, they just want to find out if it is effective at treating the disease. This is thought to be one large factor in why so few drugs make it through PhaseIII to market. If you don't know how the drug works, then you don't know why its failing. Within a trial the drug may work well for some patients, and have no effect on others, frequently the benefit is seen in so few patients that the drug is considered ineffective and dropped from the process. Any benefits that were seen are easily forgotten once the trial is branded a failure. There was however a potential to learn a lot from these studies, information which when used correctly could have meant the drug could have been brought to market.

The trial system is certainly protecting the public from potential dangers of new drugs, but it may also be indirectly harming them by being such an expensive and time consuming process that drugs that only seem to have a small benefit, or benefit only a small selection of patients, are never brought to market. In my next post I will explain how a surprising addition to the current system is already giving us the information we need to optimise the trial process and bring more drugs to market.