Oliver Brain, MRCP, PhD, is a principal investigator at the University of Oxford, Nuffield Department of Clinical Medicine, and a recent winner of an nCounter® Autoimmune Profiling Panel through a NanoString® Grant Program. He took time out from treating patients to talk to us about his translational research in the pathogenesis of inflammatory bowel disease. Dr. Brain’s current focus looks at the unintended consequences of cancer immunotherapy that can result in inflammatory bowel disease.
NS: Tell us about your research with the Translational Gastroenterology Department.
OB: Immune checkpoint inhibitors (ICI) are now a licensed therapy for many different cancers including metastatic melanoma, renal cell cancer, non-small lung cancer, and head and neck cancers, to name a few. Because these licensed drugs target CTLA-4 and PD-1 and enable T-cell activation they also have unwanted immune related Adverse Events (irAE) that can affect many different parts of the body. Quite often these drugs affect the gut, and this results in an iatrogenic IBD, characterized by abdominal pain, diarrhea, and, occasionally, bleeding.
I’m interested in studying this for two reasons: the first reason is that these patients are becoming more common as the use of ICI therapy increases. We need appropriate therapies to treat these patients and get them well enough to continue their oncology treatment. The second reason is from an IBD perspective, this provides a unique opportunity to study the development of inflammation in the gut. As an IBD specialist, most patients I see already have the disease and sometimes they may have had it for months, even years. Whenever we’ve studied the basic science behind gut immunology, we’re looking at an environment where the gut and associated biome has already changed due to the inflammation.
NS: What are the goals of your project with respect to the NanoString grant?
OB: Studying patients with immunotherapy-colitis affords us an opportunity to study samples before and after the use of ICI. Only some of the patients undergoing therapy will develop colitis. We can use patients that don’t develop colitis as a control group to study the differences in the microbiome and the immune system that associates with colitis. The NanoString project provides us with an additional opportunity to look at the colitis in more detail and improve our understanding of what is going on in the gut.
NS: What happens to the tissue in chronic inflammatory disorders such as ulcerative colitis?
OB: Although we know a lot more about the genetics behind IBD there are also environmental factors that are poorly understood including diet, smoking, and medication. The black box is what triggers someone with a predisposed state to develop the disease. Occasionally it’s an infection, like gastroenteritis, but in most cases, the symptoms just appear. Once an episode occurs then a typical sequence of events is a breach of the mucosal barrier that triggers the immune system against antigens in the gut that could be from food, bacteria, viruses, even fungi. This leads to an influx of circulating inflammatory cells and then chronic inflammation that will persist without immunosuppressive therapy. This chronic inflammation can lead to scarring and subsequent damage to the bowel. If those antigens persist in the gut, then that inflammation often recurs, leading to a chronic disease state. The key difference between studying idiopathic IBD and immunotherapy-colitis is that with the latter we know both the trigger that led to the disease and when it was given to the patient.
NS: How do the incidences of inflammatory gastroenterological disorders compare across different countries?
OB: Epidemiological data on this is convincing- whilst ulcerative colitis and Crohn’s disease appear to be increasing in incidence across the Western world, the largest increases appear in communities that are moving from a traditional lifestyle to a Western lifestyle and diet. Of the current theories, diet is being studied closely but there are many other potential reasons. Countries such as India and China that historically had a low incidence of IBD now have clear increases in the disease.
NS: That being said, can changes to one’s diet after developing IBD help reverse or mitigate the effects?
OB: There is some preliminary evidence about the influence of dietary components but at this time there is a real lack of systematic data collected that would show that changing one’s diet corresponds to a decrease in IBD flare-ups. If we understood diet better in the context of this disease then we could offer patients some relief in the form of a long-term, anti-inflammatory diet.
NS: How do the signaling pathways in chronic IBD compare to other classic autoimmune disorders such as rheumatoid arthritis?
OB: There’s quite a lot of overlap in the genetics of inflammatory conditions such as rheumatoid arthritis, IBD, multiple sclerosis, and psoriasis. One of the critical questions to be answered is why someone with a genetic susceptibility that is common to both rheumatoid arthritis and Crohn’s disease for example, will develop one and not the other. Along with the genetics there is reasonably good experimental and human data that show that the immune activation is similar despite the differences in outcomes between the diseases. For example, a drug that targets one of the effector cytokines of the IL-23 pathway is licensed and useful for spondyloarthritis, yet when it was trialed for Crohn’s disease it was detrimental for a subset of patients. So, whilst there is genetic overlap there are still enough fundamental differences that preclude us from saying that rheumatoid arthritis is “Crohn’s disease of the joints”, just as psoriasis isn’t “Crohn’s disease of the skin”.
NS: Are T-cells involved in ulcerative colitis in a similar way to how they are involved in other inflammatory disorders?
OB: T-cells have an important role in ulcerative colitis as demonstrated by animal models. Human studies have shown roles of both CD4+ and CD8+ cells as effector cells in ulcerative colitis. Originally it was believed that the nature of the T-cell response in ulcerative colitis and Crohn’s disease was fundamentally different, such that ulcerative colitis was a Th2-mediated disease and Crohn’s disease was a Th1-mediated disease. Now we know that the Th17 pathway appears to be important in both conditions and there’s a common genetic overlap related to that pathway, raising hope for monoclonal antibodies that can be effective for both diseases. T-cells are involved, and we have moved away from a binary model of their role in these diseases toward an understanding of their overlapping roles as effector cells.
NS: What do we know about the differences between the pathways that lead to classic IBD and immunotherapy-colitis?
OB: Let’s start with the genetics of IBD as a general example. We know that CTLA-4 knockout mice develop gut inflammation along with other inflammatory disorders. CTLA-4 is one of the targets of immunotherapy, and there are rare human families with CTLA-4 defects who develop a Crohn’s-like phenotype. However, the drug abatacept, used to treat some autoimmune diseases, targets the interactions between the antigen-presenting cells and T-cells to help dampen T-cell activation through the CTLA-4 molecule. While that sounds promising for treatment of ulcerative colitis and Crohn’s disease this drug was not useful in the treatment of IBD. This is an indication that immunotherapy-colitis is not exactly the same as IBD. Our preliminary data suggest that in its early stage, immunotherapy-colitis is distinctly different from ulcerative colitis. Moreover, the profound influx of circulating T-cells common to IBD is less pronounced in immunotherapy-colitis. It’s possible that we’re seeing these differences because we’re studying the progression of gut inflammation at its earliest time points.
Interestingly, while many people with immunotherapy-colitis have a short-lived disease, there is a substantial subset that go on to develop a chronic colitis that is more akin to IBD. Those patients may develop an influx of T-cells much like a typical IBD. We’re still in the early stages of understanding these differences but I think that because we can study the progression of the inflammation, we’ll gain better insight into the triggers of gut inflammation.
NS: Approximately what percentage of patients treated with immunotherapy develop some sort of immunotherapy-colitis? Is this group also more prone to develop other chronic inflammatory disorders?
OB: The number of patients developing gastrointestinal disorders after immunotherapy depend on the therapy used. With a combination of CTLA-4 and PD-1 inhibition, like what is used in melanoma, the rate can be as high as 45%; PD-1 treatment alone is associated with an incidence to 15-20%. It does not appear; however, that a preexisting autoimmune disease puts a patient at higher risk of developing immunotherapy-colitis. That’s important because those patients should not be excluded from receiving cancer immunotherapy should they need it.
NS: Why is immunotherapy-colitis the most common of all the autoimmune diseases one could develop with ICI treatment?
OB: I suspect it has to do with the epithelial interface and the gut microbiome. First, the other most common side effect is dermatological (rashes) and that’s the body’s other main epithelial barrier. While the epidermis is not exposed to the same density of bugs that the gut is, our skin clearly has a microbiome of its own. Secondly, when it comes to gut inflammation, much like IBD, the areas that are most commonly affected by enterocolitis appear to be the large bowel and distal small bowel, where the population of gut bacteria is the densest. There’s very early data suggesting that the makeup of your gut microbiome influences whether you develop immunotherapy-colitis. Part of our NanoString grant is to add to those data and see how that plays out.
NS: What can we learn about treating autoimmune diseases by studying immunotherapy-colitis?
OB: One important question is if we’re treating ICI patients with the best therapy for them. There’s almost certainly a better, more targeted way of treating these ICI side effects and a more accurate understanding of the immunotherapy-colitis immunopathology should lead to better treatments. This work may not lead to different treatments of idiopathic IBD but the ability to analyze how a normal gut and microbiome transform into a disease state as a result of a known initiating event. This will allow us to unpick the key crosstalk events of inflammation that we can’t otherwise study. Now, because we have patient samples before and after immunotherapy-colitis, we have a real opportunity to learn. The NanoString grant and nCounter technology will augment our other methodologies such as single cell RNA sequencing and flow cytometry. We want to be able to ask more important questions about what treatments wi
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