Immune System Model - DSRCT Wiki Project

Polly Matzinger - Immune 'Danger Theory' [The evolution of the danger theory - PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4803042/#S9) > I think that the model has the most potential impact in therapy for hemophilia, where danger-based clinical trials are beginning to occur, and for tumor therapy. However, the tumor experts do not seem to be listening. Approximately 10 years ago, I suggested that we have the capacity to clear 80% of tumors with immunotherapy, yet we are not doing it. The reason is that immunotherapy is not being properly used. What you think influences what you do. If you think about the immune system in one way you will do something different to someone who thinks about it in another way. > ## How do you think that tumor vaccines should be used differently? > > Two of three things could change. > > First, most tumor vaccines are used in the same way that most antiviral vaccines are used. People get a priming shot and then a boost, and that is it. This works for vaccines against viruses but it would not work for tumor vaccines. When you vaccinate against a virus, you prime to activate the T cells specific for the virus, and boost to expand the number, after which they expand, contract a little, then go on to a long-lasting resting memory state. If the virus arrives, it does the damage that wakes up APC that in turn reactivate those vaccinated resting memory T cells. Thus, for a viral vaccine, producing a large population of virus-specific resting memory cells is great because the virally-induced damage is immunostimulatory. > > However, vaccinating against a tumor is a different story. First, this needs to be a tumor against which the person still has a few specific T cells, because an early growing tumor is a healthy tissue not sending alarm signals, and therefore is constantly inducing tolerance to itself. Hoping that the tolerance is not complete, you vaccinate to increase the number of the few remaining tumor- specific T cells. Then you boost to expand this population further. Yet, even though studies using tetramers can show an increased frequency of the tumor-specific T cells in blood, the tumor is not cleared. I think there are three reasons for this. > > First, after the boost, the cells do what they are programed to do, which is kill one round of tumor cells then go into a resting memory state. The killing done by a cytotoxic T cell is apoptotic; it does not cause the release of alarm signals so it does not boost the response, which consequently displays typical immune response kinetics and wanes after about 2 weeks. All those killer cells that were activated by the vaccination go back into a resting memory state. This is fine if you have killed the last tumor cell but, if not, the tumor will continue to grow. So you need to boost, and boost and keep boosting. > > There was a clinical trial, which did not get the recognition it should have, showing that this works. Maurizio Bendandi (Pamplona, Spain) used a vaccine for people who have B cell lymphoma. This is an individualized tumor-specific vaccine made by taking the antibodies produced by the patient’s lymphoma cells and coupling them to keyhole limpet hemocyanin. This produces the vaccine, which is specific to the lymphoma and individual to the patient. The original protocol, which was invented by Ron Levy at Stanford, is better than most, as patients get five injections, rather than the standard two. Although this works on some patients, many relapse. Bendandi managed, after 3 years, to get board approval to keep boosting with the vaccine. Each patient was their own control. Each had relapsed previously and was treated again with chemotherapy. Vaccination began after 3 months when their immune systems had recovered. Bendandi kept vaccinating them month after month, and got an amazing result! Eighteen of the twenty patients had not relapsed by twice the amount of time their first relapse took place [[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC4803042/#R5)]. Unfortunately, one subject died and after writing to Bendandi, I learned that they had run out of his vaccine at 2 years, and the patient died at 2.5 years. This approach certainly looked like it worked but for some reason it has not gotten much attention. > > The danger model supports this approach, as it says you have to keep boosting. The second thing you have to do is bear in mind, as with vitiligo, that even if you have an activated immune system it will only locate to certain places. So you need to do damage or something to the tumor to direct the activated cells there. Otherwise you can boost and activate all the tumor-specific cells but if the endothelial cells in the blood vessels are not activated the lymphocytes are not going to extravasate and reach the tumor. > > The third thing, and this part is difficult, involves the new part of the danger model. The tumor is a tissue and tissues have ways of communicating with the immune system so that a local immune response clears a pathogen without destroying the tissue itself. > > Thus a tumor will also have mechanisms to prevent immune- mediated destruction. When people tell me that their tumor is very immunosuppressive because it makes TGF-b, I bet them a bottle of champagne that the tumor is either a gut or bladder tumor. It is not making TGF-b because it is a tumor, but because TGF-b instructs B cells to make IgA, and this is exactly the kind of immunity that is appropriate in the gut and the bladder. > > What we need to do now with tumor vaccines is find a way to overcome the normal tissue signals that instruct the immune system to produce a nondestructive response. > > In the vaccine, you need to put in substances that are going to give a strong Th1 or delayed- type hypersensitivity killer response to kill the tumor. You need to do it in such a way that those cells ignore those tissue educating signals. We know how to make vaccines, how to boost, how to do damage, but we do not yet know much about the signals that the tissues use to educate the immune system, so we do not yet know how to overcome them. > > ## Perhaps some sort of adjuvant could be used? > > People are using adjuvants. But none of those adjuvants are designed to deal with tissue-education signals. I’m not sure what sorts of adjuvants we would want to use there. We will first need to do some basic research to get a handle on the signals that tissues use. Once we have figured those out, we will be in a position to find agents that modify them, so that we can control the response to a vaccine. In the meantime, people are trying to find adjuvants that do not do damage. I say good luck to them. An adjuvant that does not do damage is unlikely to give an immune response. Unless we start using the body’s own adjuvants – meaning the alarm signals that are the result of damage. Once we get a catalog of what the alarm signals are, we should be able to start using them as nondamaging adjuvants.