Sunday, 18 January 2009

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 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.

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