Toward New Therapeutic Approaches for Autoimmune Diseases

Carl F. Ware, PhD; Salvatore Albani, MD, PhD

Disclosures

July 27, 2012

Editorial Collaboration

Medscape &

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Carl F. Ware, PhD: Hello. I'm Dr. Carl Ware, Director of the Infectious and Inflammatory Disease Center at Sanford-Burnham Medical Research Institute. Welcome to this segment of Developments to Watch from Sanford-Burnham and Medscape. Joining me today is my colleague, Dr. Salvatore Albani, Director of Translational Research and a practicing rheumatologist.

Today's program will focus on key research efforts in identifying and manipulating mechanisms implicated in the development of autoimmune diseases and how this research will affect clinical practice. Thank you for joining us, Salvo.

Salvatore Albani, MD, PhD: Thank you, Carl, for having me here. My pleasure.

Dr. Ware: One of the things that we want to talk about today is the process of developing autoimmune disease. If we focus on a disease like rheumatoid arthritis -- tell us how that differs from other joint diseases.

Dr. Albani: Let's find the definition first. Autoimmune disease, by its own words, is a process in which the body attacks itself. The words "disease" and "autoimmunity" must come together. Autoimmunity itself is not a disease because it happens every moment in our lives. It's when we learn what self and nonself are and when danger and nondanger can be discriminated. Autoimmunity and arthritis, specifically in this context, is the equivalent of a civil war, where the body attacks itself using its own resources, like an army going rogue and pillaging its own cities.

Dr. Ware: How would you differ that from, say, osteoarthritis?

Dr. Albani: That's precisely the point. Osteoarthritis is more a process of wear and tear, the unavoidable passing of time, which determines progressive destruction of the joint as opposed to active inflammatory processes, which destroy it from outside.

Dr. Ware: When we talk about the immune system, there are many components. What are the components that go wrong in autoimmune diseases?

Dr. Albani: For diseases like arthritis, I would say they're called systemic because they affect the whole body. The immunology system itself is affected and contributes to it as a whole. There are 2 general arms. What is called the innate immunity is powerful but not very sophisticated. It can generate a lot of inflammation and damage, but it cannot govern it. It cannot modulate it. Conversely, adaptive immunity is a process in which the body learns and evolves its responses based on needs and evolution. Adaptive immunity is, for example, the development of a dimmer, which, like a light, can be regulated. It can tune up and down the intensity of responses for an immune disease or an autoimmune disease.

Dr. Ware: In those cells that are involved in adaptive immunity, you're referring to T cells and B cells. What's the difference between T and B cells?

Dr. Albani: They are 2 different types of cells. They both can learn and evolve based on what they have learned. B cells act mainly by producing proteins that are released into the blood, which are antibodies. Some of them can bind components of our own body and generate damage. B cells can also produce other proteins, which are network proteins called cytokines.

T cells are a bit more complicated. Their action appears more vague, but it's not. They can talk to each other by talking one to the other, by contact. In some cases, they can kill each other. In other cases, they modulate responses by simply brushing one over the other and talking amongst themselves. Finally, they can also produce cytokines, those proteins that communicate in networks.

Dr. Ware: In a disease like rheumatoid arthritis, what are we doing these days to control the immune response? Is there a way to establish tolerance vs immune suppression? How do those two differ?

Dr. Albani: First of all, I think you will agree when I say that it is a privilege to work in this day and age. We are seeing changes and evolutions in science, which usually takes decades, many decades, and is happening in a lifespan of an individual scientist. This, of course, is a privilege, trying to contribute to these with a patient in mind.

What we have seen in the last 10 years is a dramatic change in which we applied basic research knowledge to the clinic. The first -- almost extreme -- example is the ability to interfere with one of those proteins produced by cells called cytokines, which can move up an inflammatory response. By interfering with these cytokines, we can bring down the level of inflammation with a consequent clinical change. The first of these therapies is a biologic, an anti-tumor necrosis factor (TNF) inhibitor, with TNF being the cytokine target.

Dr. Ware: In these inhibitors that block cytokine signaling, they're disrupting the communication systems between the various cells and the T cells, B cells, and engaged cells in the joints -- for example, the synovial sites.

Dr. Albani: I have already outlined in one sense the complexity of the issue. It is simplistic to say that we have something that soaks up free TNF in the blood and that we took care of the problem. In reality, as you alluded to, TNF contributes to signaling, to cross-talk amongst cells, to mechanisms that can reverberate themselves, amplifying the level of inflammation. When we touch something in the immune system, we always have to think that the system is redundant so the blockade can be bypassed. In fact, the therapy doesn't work for everybody. Also, there is a consequence to this blockade up- and downstream.

Dr. Ware: These TNF inhibitors are really quite powerful and have consequences -- side effects, I guess we could call them -- due to the fact that TNF is also required to control infectious disease. Is that one of the side effects of immune suppression caused by TNF inhibitors?

Dr. Albani: Thank you for this question because it gives us an opportunity to step back for a second and look at the differences between suppression and tolerance. This is not just semantics. When we talk about suppression, we mean our ability -- or attempt -- to block a given pathway and eliminate from circulation, say, a cytokine. When you do that, as you alluded to already, you change the shape, the quality, and the strength of an immune response.

Tumor necrosis factor, TNF, as the name says, is a very important cytokine to defend us against infection and cancer. Without being alarmist within a range of objectivity, we can say that, in a very small proportion of patients, some side effects, if you want to call them that, have been noted. They relate to the ability of tuberculosis, for instance, to reactivate itself; prevalence of certain fungal infection; and in some cases, lymphoma. These effects are more prominent in a very small proportion of patients -- the pediatric population rather than adults.

Dr. Ware: The immune suppression here is not as dramatic or radical as chemotherapy that cancer patients get. It's more focused on certain types of infectious diseases that may recur. I think one of the things that I've been most amazed by with the TNF inhibitors is their breadth of use in treating different autoimmune diseases, such as rheumatoid arthritis, which we've talked about. TNF blockers seem to be always associated with the concept of rheumatoid arthritis and the inflammation there. But Crohn disease and psoriasis are also treatable with TNF inhibitors. How do they relate, these very different diseases?

Dr. Albani: As I mentioned a little while ago, there is a redundancy in the immune system, as there is in many of the other physiologic pathways. Certain tools are used in certain situations regardless of the nosologic background, meaning which disease we're talking about. If you need inflammation, you need TNF, in different settings. Again, this underscores the importance of discriminating between suppression and tolerance. When you suppress one pathway without discriminating when and how you're suppressing it, the effect can be unpredictable. Conversely, if you try to restore a natural mechanism to control inflammation, which by nature is multipronged, you can aim at what we call tolerance, which is an approach that is sought after in therapeutic development.

Dr. Ware: In the treatment of patients responding to TNF inhibitors, you'll have a subset of patients that responds very well and another subset of patients that doesn't respond or only partially responds. Is this suggesting that other mechanisms of inflammation may be at play or may be involved in these same sorts of diseases?

Dr. Albani: You can look at at least 2 dimensions that are parallel and yet intersect. One is the fact that, as I mentioned, pathways can overcome each other and bypass blockades and yet accept a pathogenic effect. Consequently, there is the need for tolerization vs suppression.

The other dimension is that we are using, specifically for rheumatoid arthritis, diagnosis and grading criteria that were generated by people wearing wigs in the 1700s, with all due respect. We're not really exploiting the evolution of molecular knowledge.

Instead, what we look at are phenotypes. All of the patients look the same when they walk in our offices so we diagnose them with the same diseases, But only 50% respond well to an anti-TNF and the rest do not. Are they different diseases? Maybe they are.

Dr. Ware: Tell me a little bit about how you see the initial trigger for an autoimmune disease vs the actual disease reaction. Are we targeting those in current research?

Dr. Albani: This question underscores an evolutionary step that has occurred in the last years and is part of how we develop a therapy. The conventional model is that you have a discovery in vitro in a petri dish. You develop an animal model. Then you develop a therapy that you test in humans using exactly the same approach.

In autoimmunity, it's very easy to trigger a disease in an animal with a given antigen, with a certain protein, and you then treat these diseases with the same antigen, inducing tolerance. However, for human diseases, we have no idea what the trigger is. It doesn't work to presume that in the case of arthritis it is collagen and in other cases there are other antigens. Most likely these triggers are multiple. They are multifactorial, meaning there is an overlap of genetic and environmental factors, and they are most likely gone by the time the patient walks into our offices.

The focus needs to shift if you want to really affect these mechanisms, from looking for a holy grail that does not exist toward looking for a mechanism that is common and that contributes to inflammation independent of its trigger.

Dr. Ware: This idea of personalized medicine, that having a better genetic profile for a patient may give you an advantage as a clinician in finding and selecting the right therapies -- tell us a little bit about your research and how you're approaching this specific problem.

Dr. Albani: What we try to do is allow our research to be inspired by unmet medical needs. We identified 2 dimensions that have been developed. The first is an attempt to interfere therapeutically with a circuit of inflammation that is trigger-independent, meaning that we don't care what started it, yet it is there. This is based on recognizing fragments of proteins that are present in any living cell and are overrepresented whenever there is an inflammation or infection in that area. It is a very smart system used by the immune system to amplify inflammation independent of the trigger.

The idea is that if we understand this loop better, we can interfere with it by inducing tolerance to it. Part of our work over many, many years has been to identify this mechanism and then to identify also a tool that could be applied in the clinic. This tool is a short, synthetic peptide that is part of this self-inflammatory loop. If we can induce tolerance, if we can retrain the immune system of the patients toward respecting and tolerizing these peptides, we may downregulate the level of inflammation as a whole.[1]

To go back to your original question, this is a kind of personalized medicine. In the clinical development phase 1 trial,[1] we selected patients for treatment based on the presence in their blood of the same reaction before treatment that we wanted to effect. We have basically eliminated, before even starting, those patients for whom we couldn't find a detectable response. I wouldn't say it's personalized medicine, but it is knowledge-targeted biotherapy.

Dr. Ware: The immune system goes through the development of tolerance usually during early life, childhood, and then we become somewhat hardened. Do you think your new therapies might approach this to reeducate adult immune systems?

Dr. Albani: Perhaps. It's a very good question. The example I could give is to take the army of invaders that has turned against its own people and, rather than kill them, send them back to college. Maybe it's not returning to infancy but to a mature understanding of what should not be destroyed.

Dr. Ware: As for the clinical applications of your work, where would you see a clinical trial evolving?

Dr. Albani: The first immediate application has been an attempt to induce tolerance in an important disease like rheumatoid arthritis. We have gone from proof of concept all the way to the conclusion of phase 2 trial,[2] in which we tested, for the first time, the clinical efficacy of your approach. That has been quite encouraging, both from the clinical and the immunologic standpoint. We have proof, in other words, that we're able to reeducate the immune system the way we were hoping to.

Dr. Ware: Of late, there's been a lot of talk about utilizing dendritic cells as a mechanism of presenting these tolerizing peptides and epitopes that you talk about. Tell me a little bit about dendritic cells. What do they do?

Dr. Albani: Dendritic cells are the smart cousins in the family of innate immunity. They act as an interface between inflammatory stimuli and adaptive immunity, so they're able to select and present fragments of proteins to T cells and affect not only the strength, but also the quality, of how T cells react. Consequently, a very smart approach toward inducing tolerance in an autoimmune disease is to target these cells, because they can affect the intensity and quality of the immune response on both ends.

The limitations are that they need to be alive and they need to be, ideally, from the same individual. Obviously, this is personalized medicine to the extreme. The limitation, of course, is that on a very large scale it's probably not feasible.

Dr. Ware: Do you think there's room in the treatment of severe autoimmune diseases, where patients are failing all the therapies that we can provide for them, to utilize stem cells to reconstitute the hematopoietic system? Is this close or is this still in the future?

Dr. Albani: It was highly fashionable in the early 2000s. Stem cell transplant for rheumatoid arthritis and scleroderma, which has a significant lung involvement, were among the diseases tested. The outcomes have been mixed. It's a very aggressive approach, so it has a very high level of mortality compared with not doing anything, and there are some reactions that are undesirable, such as macrophage activating syndrome in certain cases. By tweaking the protocols, the efficacy and safety have increased. Still, it's limited to a select number of patients, a very small one.

Dr. Ware: In the popular press, you'll often see debates about whether environment, contaminants, and pollution, vs genetics, is responsible for the development of autoimmune disease. How do you see those complex factors playing out?

Dr. Albani: This is another exciting development of our times. The interface is called epigenetics. The best example I can bring is twins who are completely identical by genetic makeup and yet one, say, has arthritis and the other does not. And when we study their immunology, it is indeed different. The way the environment affects gene usage, gene expression, is a fundamental area in which we have to learn a lot. Maybe the key is to understanding the processes in which genetics, environment, and immunology all coalesce and work together.

Dr. Ware: What do you think are the next steps in the development of therapies and treatments for autoimmune diseases?

Dr. Albani: What I dream of and what our passion is, is to make a difference for the patients. The research is inspired by unmet medical needs and is targeted by interfacing molecular knowledge with clinical phenotypes. Where we are going is to leverage these instruments and probably redraw some of the disease classifications that are based exclusively on phenotypes and then accordingly target our therapies.

The markets, if you think in pharmacologic terms, will be smaller, but the level of efficacy will be much higher to the benefit of the patients, first and foremost, but also to society. The development of tools that we like to call "theragnostics," meaning that they affect the therapy and diagnosis at the same time, is one of the objective and tangible needs of the future.

Dr. Ware: This would involve understanding an individual patient's genetic makeup and their expressed proteins in a given situation. All of that information collected together, which you call theragnostics (which I think is a very cool term), must encompass a huge amount of data. How is a physician going to handle this type of information? Can we distill it?

Dr. Albani: That is our job. If you plot the speed of growth of the various -omics -- immunomics, genomics, etc. -- vs the clinical knowledge, the former is logarithmic growth and the other is almost flat. There is a divergence that we need to bring together. That is a fundamental task that we have. For the physician, for the practitioner, all of what we are doing can be materialized in a chip. Ideally, you'd put a drop of the patient's blood onto the chip before you give the therapy, and it would tell you which therapy to give.

Dr. Ware: This sounds like a real collaboration between basic scientists, translational scientists, physicians, and physician scientists, so that we can blend together all of this growing knowledge of information, training in medical schools all the way through to retraining current physicians and practitioners. Tell me a little bit about the Translational Research Alliance [a collaboration among Sanford-Burnham; University of California, San Diego; Scripps Research Institute, and the University of Southern California] and how that's impacting this.

Dr. Albani: Let's very briefly define translational medicine first. If you imagine a deep valley, on one end there is the idea and on the other end there is the patient. Translational medicine is the bridge. The bridge is a 2-way bridge. It goes from idea to product, from unmet clinical need back to the lab. An alliance of this kind aims at creating bridges and interfaces that go both ways, engaging clinicians and scientists together toward a common goal. We at Sanford-Burnham have developed and keep developing these sorts of alliances, which we leverage on the strength of all the institutions and people involved.

Dr. Ware: What can practicing clinicians look forward to in the coming years?

Dr. Albani: These are very exciting years. The first thing one can expect is more of the same, meaning important biologics in the area of autoimmunity where the efficacy is as good as what we have and probably the safety and tolerability profiles are better. That's exciting but not super-exciting. What I think will really reshape the field and the way we practice medicine is the ability of interfacing knowledge with the phenotypes and giving physicians tangible tools to improve the way they can make decisions, both in terms of diagnostics and which therapies to choose.

Dr. Ware: That was a very interesting topic. Thanks, Salvo, for joining us and participating in the program today.

Dr. Albani: Thank you for having me here.

Dr. Ware: We would both like to thank you for joining us today. I hope you will join for additional programs in the Developments to Watch series on Medscape.

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