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) Context: Interview with [Polly Matzinger](https://en.wikipedia.org/wiki/Polly_Matzinger), famous immunologist who proposed the danger model building on models of immunology. > 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 TEST This is a sidenote. 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. --- Interesting corollary: [One Universal Antiviral to Rule Them All? \| Columbia University Irving Medical Center](https://www.cuimc.columbia.edu/news/one-universal-antiviral-rule-them-all) Researchers found that people with a rare mutation (few dozen ppl around the world) - **ISG15 deficiency** - suffered from a mild but persistent systemic inflammation state vs people without the mutation. TEST This is a sidenote. Rare mutation in people causes deficiency in an immune regulator called ISG15 which causes them to have more persistent inflammation response because it is part of the body's natural response to resolving again to a non-inflamed stated post infection. Wouldn't want to be in a persistent inflammation state when infection resolves, energetically expensive/not optimal for a normal healthy person. So they maintain that persistent IFN-I response unnecessarily. ISG15 = IFN-I–stimulated gene 15 Paper abstract: Type I interferons (IFN-Is) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of thousands of IFN-I–stimulated genes (ISGs), whose aggregate function results in the control of viral infections. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, often self-resolving, mild autoinflammation. Turning off ISG15 entirely is mapped to production of more than 60 proteins, and 10 of these identified to be primarily responsible for the broad antiviral protection, uses these 10 proteins as the idea for a therapeutic to boost these to confer similar effect. > “The type of inflammation they had was antiviral, and that’s when it dawned on me that these individuals could be hiding something,” Bogunovic recalls. When he and his colleagues looked at the individuals’ immune cells, they could see encounters with all sorts of viruses—flu, measles, mumps, chickenpox. But the patients had never reported any overt signs of infection or illness. > > “In the back of my mind, I kept thinking that if we could produce this type of light immune activation in other people, we could protect them from just about any virus,” Bogunovic says. > > In his latest study, published Aug. 13 in [Science Translational Medicine(link is external and opens in a new window)](https://www.science.org/doi/10.1126/scitranslmed.adx5758), Bogunovic and his team report that an experimental therapy they’ve developed temporarily gives recipients (hamsters and mice, so far) the same antiviral superpower as people with ISG15 deficiency. When administered prophylactically into the animals' lungs via a nasal drip, the therapy prevented viral replication of influenza and SARS-CoV-2 viruses and lessened disease severity. > > Bogunovic’s therapy is designed to mimic what happens in people with ISG15 deficiency, but only for a short time. > > Instead of turning off ISG15 directly—which leads to the production of more than 60 proteins—Bogunovic’s therapeutic turns on production of 10 proteins that are primarily responsible for the broad antiviral protection. > > The current design resembles COVID mRNA vaccines but with a twist: Ten mRNAs encoding the 10 proteins are packaged inside a lipid nanoparticle. Once the nanoparticles are absorbed by the recipient’s cells, the cells generate the ten host proteins to produce the antiviral protection. > > “We only generate a small amount of these ten proteins, for a very short time, and that leads to much less inflammation than what we see in ISG15-deficient individuals,” Bogunovic says. “But that inflammation is enough to prevent antiviral diseases.” > > But the technology’s drug delivery and absorption properties still need optimization. When delivered to animals via nanoparticles, the 10 proteins were produced in the lungs, “but probably not at high enough levels that makes us comfortable going into people immediately,” Bogunovic says. > > “Once the therapy reaches our cells, it works, but the delivery of any nucleic acid, DNA or RNA, into the part of the body you want to protect is currently the biggest challenge in the field.” The researchers also need to determine how long the therapy’s antiviral protection will last, currently estimated at three to four days. Summary - researchers looking in to mRNA of the most potent 10 proteins implicated in the process and using the latest LNP technology to produce these proteins in cells in the body. Could we design a similar set of proteins for ramping up the immune system against cancer targets? Current challenges and areas of clinical development - transient production, tissue delivery etc. Lessons for cancer research - serendipitously uncovering processes in nature (genetic mutations etc) that confer general (or specific) cancer resistance and mapping the causes to the protein level, then using mRNA to produce those proteins for a desired state. Bats, elephants etc more resistant to cancer - any insights? Seems harder to find post oncogenesis mechanisms (p53 multiple copies abetting genetic instability prevent the arising of cancer but not so much once it is already established). Interestingly, lack of efficacy when delivering individual mRNAs from the 10 but collectively delivering the 10 together recapitulated the desired effect. Reason it is interesting - immune system can be mobilised to attack cancer but natural and important feedback loops then tamper down the response to return to a normal state. Cancer requires an ongoing and persistent immune system response to eradicate the huge number of cells and environments it needs to. Theoretically, keeping it on and potent for too long would be dangerous, autoimmune diseases cause problems like this and face the opposite problem. Cytokine storms etc. Second order effects hard to predict - lindy principle says that there is a reason for not using up immune system resources. But cancer is a dire proposition - a therapy designed to keep you inflamed/sick against the cancer would be a tough treatment but presumably worthwhile if it can be tolerated, cycled, switched off etc. Chemo a similarly debilitating treatment lens. Modifying feedback loops systemically is hard! Especially with the complex immune system. Systemic inflammation pro cancerous mechanisms to be balanced with immune system ramp up trade off. Locally induced inflammation such a promising area but hard to develop clinically. Intratumoural injection etc. How to make the response exquisitive enough to the cancer cells only? Cancer specific antigens very potent - claudins, checkpoints etc. Identifying extremely exquisite targets important and then trying to modify only the immune regulatory feedback loops for these contexts to prolong persistence of immune response. [One universal antiviral to rule them all? \| Hacker News](https://news.ycombinator.com/item?id=45026792) Hacker news interesting comments too. When bats release interferon upon infection, other cells quickly wall themselves off, driving faster virus replication in less susceptible/protected systems ie humans (by evolutionary principles?). [Coronavirus outbreak raises question: Why are bat viruses so deadly? \| ScienceDaily](https://www.sciencedaily.com/releases/2020/02/200210144854.htm) "A new University of California, Berkeley, study finds that bats' fierce immune response to viruses could drive viruses to replicate faster, so that when they jump to mammals with average immune systems, such as humans, the viruses wreak deadly havoc." "Some bats are able to mount this robust antiviral response, but also balance it with an anti-inflammation response," said Cara Brook, a postdoctoral Miller Fellow at UC Berkeley and the first author of the study. "Our immune system would generate widespread inflammation if attempting this same antiviral strategy. But bats appear uniquely suited to avoiding the threat of immunopathology." Perhaps less relevant for cancer, important to note for immunology research and second order effects. [Scientists Discover Why Bats Don't Get Cancer - YouTube](https://www.youtube.com/shorts/jE07W5wHcYU) [We FINALLY Understand Why Bats Live So Long - YouTube](https://www.youtube.com/watch?v=UYFRLEQBDpc) Bats interesting - had to evolve their immune systems to be hyper efficient to survive the extreme metabolic damage caused by their flight. Follow up - outline Dr Ben Miles - Good channel. Discuss?