Making Precision Medicine a Reality in Immune-Mediated Diseases

To address the debilitating, painful, and sometimes life-threatening outcomes of immune-mediated diseases, better therapies are needed, along with the ability to tailor treatments to individual patients - an approach known as precision medicine.

A new generation of technologies are enabling us to dissect and better understand the mechanisms which drive immune-mediated diseases and how they differ between individual patients.

Luke Devey, M.D., Ph.D., Vice President, Head of Immunology Translational Science, Janssen Research & Development, LLC shares insights into how Janssen researchers are harnessing those technologies in our quest to find the right medicines for the right patients, and the future innovations that are needed to make this a reality.

The importance of precision medicine for immune-mediated diseases
Immune-mediated diseases affect hundreds of millions of people worldwide and are the result of complex interactions between multiple different immune cell types, mediated by a vast array of signaling molecules. The ensuing inflammatory “storm” causes tissue damage and pain in the skin, joint, or gut, and in turn, the severe symptoms that many people live with every day. Furthermore, autoimmune diseases can be associated with stigma, isolation, and decreased productivity, leading to anxiety, stress, and depression.

A diverse range of factors such as genetics, co-morbidities and, the microbiome, as well as environmental factors and lifestyle choices, contribute to the potential inflammatory mechanisms driving immune-mediated disease in a particular patient.

These complexities mean that a particular treatment might be successful for some patients, but not others. Precision medicine – optimal treatment that is tailored to the individual – seeks to ensure that the medicine prescribed to an individual patient is addressing the molecular problem that is the root cause of their disease.

In cancer, the companion diagnostics that make precision medicine possible – such as DNA sequencing to identify an oncogenic mutation – are almost always designed to detect the disease target. But selecting the best drug for a patient with immune-mediated diseases is much more complex. For example, 250 single-nucleotide polymorphisms (SNPs), the most common type of genetic variation among people, are known to contribute to inflammatory bowel disease (IBD). These SNPs map to a diverse range of biological functions, from the barrier function of the intestine to immune regulation and cytokine signaling. Each of these biological processes alone may only contribute a small part of disease pathogenesis, but in combination, together with the other external factors listed above, they cause disease. Since each patient will have their own distinct assortment of SNPs and other pathogenic contributors, the most dominant therapeutic targets will likely be different among individual patients.

The huge increase in our understanding of immunology in recent years, coupled with advances in technologies that measure immune function with high resolution (notably genetics and a new generation of “omics” techniques), are defining a new era. The data we can generate for each patient has unprecedented complexity and depth: whereas conventional blood tests from the past might have generated tens or at most hundreds of data points for the physician to look at, these new techniques might generate millions! This is true “BIG data” and requires a whole new set of mathematical and computational approaches to interpret it. Collectively, we call these approaches “high dimensional biology”.

By combining these new laboratory techniques with computational approaches, we will soon be able to understand the molecular drivers of disease for individuals, not just a “one-size fits all” for the entire population. In this new era, we hope to provide therapies for diseases defined not only by their clinical presentation and symptoms, but by their precision medicine-based molecular mechanisms.

Impact for patients
Enabling precision medicine isn’t just a theoretical exercise; it has the real potential to help people. My teenaged neighbor has Crohn’s disease with strictures, which are areas of narrowing in the intestines. Although he is doing okay at the moment, he has experienced some major bumps in the road. His mom worries about how the disease is going to affect his life as he, like many patients, navigates flares of his disease.

Insights into the molecular causes of disease, accurate and early diagnosis, and prediction of treatment response are all critically important to making precision medicine a reality for people like my neighbor. Janssen researchers, together with our partners in academia, the biotech sector, and contract research organizations, are advancing the science that will enable us to address the worries that patients and their families face. We have an incredible opportunity not only to develop new medicines, but also employ our resources and ingenuity to deliver them to the right patients at the right time – before their disease can lead to permanent organ damage and scarring.

Progress in precision medicine
The successes of molecularly targeted immune therapies have provided invaluable insights into the mechanisms responsible for seemingly disparate immune-mediated diseases. And the fact that the same therapy can be successful across multiple diseases show that the same immune pathways may drive distinct different pathologies.

Advances in new technologies are now revolutionizing our insights into the mechanisms of immune-mediated diseases. Genetics, transcriptomics, proteomics, and metabolomics are now well-established and used routinely by researchers. Newer technologies, like single cell RNA sequencing, when applied to thousands of cells in one blood or biopsy sample, can reveal the mechanisms of disease in exquisite detail, enabling researchers to build detailed computer simulations of how those diseases occur. With these insights, researchers can determine potential molecular targets for therapy, identify patient subsets with different disease-driving immune mechanisms, or even simulate the effects of combining multiple drugs with different mechanisms of action. When all of this information is integrated by using novel computational approaches, these “omics” approaches provide the opportunity to move from defining immune-mediated diseases by their clinical presentation and symptoms to the precise underlying disease-driving immune mechanisms: known as a molecular taxonomy of disease.

Janssen is also committed to developing therapies for diseases driven by pathogenic auto-antibodies. In many cases, which specific antibodies are actually driving disease, versus those which are benign bystanders is not clear—and understanding this question would enable us to more specifically target the pathogenic antibodies. At Janssen, we are probing deeply into techniques to characterize the specificity of auto-antibodies and their functional characteristics. This is a great example of precision medicine: being able to define a disease by its mechanism – and treat it accordingly with a drug targeted directly at the root cause.

To better define and understand diseases driven by the many different types of immune cells, a key investment we are making is in molecular atlases of disease. Through our Cartography collaboration with scientists at the University of Oxford, we are creating a detailed cellular map of genes and proteins responsible for a broad range of pathologies. Cartography is using a new technique called CITE-seq, which is capable of measuring cell surface proteins along with single cell RNA sequencing to uncover the pathogenic pathways active in cells in blood and diseased tissues.

As we integrate these data, our ambition is to build an in silico resource that can be interrogated rapidly to provide the evidence we need to make rigorous decisions about which of the drugs in our pipeline to develop for which diseases and in which specific patient populations. Since the data we are generating are so comprehensive, it is possible to answer questions quickly across target pathways and diseases. We can ask questions of our computational biologists before even lifting a pipette in the lab, which expedites decision-making about the medicines in our R&D pipeline. As we build the atlas, we anticipate that we will be able to compare key mechanisms between therapeutic areas. For example, T-cell exhaustion, which is pathogenic and promotes tumor growth and spread in oncology, could inform therapeutic goals in immunology. Conversely, T-cell activation, which is pathogenic in immune-mediated diseases, may inform our therapeutic approaches in immuno-oncology.

In order to describe endotypes of disease - meaning, smaller groups of patients within a larger disease indication that are driven by defined molecular mechanisms - we need to scale to hundreds or thousands of patients to achieve statistical power. If we could define my neighbor’s disease much more precisely – with a molecular endotype of his Crohn’s disease – we could prescribe him a specific therapy designed just for his distinct disease driving mechanisms with the potential for greater efficacy and fewer unwanted side effects.

From arm to insight: scaling up “high dimensional biology”
Scaling up to generate high dimensional data across clinical trials is a challenging, end-to-end engineering problem that we call “from arm to insight.” Each step of the process will likely require significant innovation. It all begins with a patient, from whose arm we collect a blood sample or a biopsy from a diseased organ or tissue such as the skin or intestine. Samples may need to be collected into a novel specimen tube, perhaps containing a newly invented preservative, and biopsies may require cryopreservation to preserve the cells intact. Accelerated logistics may be needed to get samples to central labs quickly and in good condition. Wet lab processes will need to be engineered to enable cutting-edge analyses at scale, high reproducibility, and affordable cost.

Optimizing these elements while enabling clinical trial execution to continue seamlessly is critical. Once we have generated all the data from these sophisticated laboratory analyses, we will need the computational approaches to analyze and decode them and provide the actionable insights quickly, to enable us to move our therapeutic programs forward more effectively.

It’s ambitious, but software and computing technology could eventually spot patterns in the clinical and molecular data and automatically push them out to researchers. Some technologies may be ready now, perhaps borrowed from other sectors like finance and tech. Just think about how your credit card company can detect changes in your spending habits which might indicate that your card has been stolen, or how you receive targeted advertising on Google after you walk out of a store. We hope to bring the same expertise to bear on complex high dimensional biology problems to help solve the complex puzzles inherent with the full implementation of precision medicine.

Making precision medicine a reality
At Janssen, we have identified five areas which will require specific focus for precision medicine to become a reality for immune-mediated diseases:

  1. Deployability: We must determine how to collect peripheral blood mononuclear cells (PBMCs) and biopsies from patients in clinical trials much more routinely to deliver more reproducible data. This may occur by using a new preservative or type of blood tube, a clever logistics solution, or a work-around that enables us to get the same insights from other modalities without needing PBMCs.

  2. Identifying “rosetta stones” to translate information from data generated from different sources or technologies. For example, predicting single cell sequence data from bulk tissue sequencing or tissue activities from blood data will be invaluable to unlocking insights from previously collected data repositories and simplifying future sample acquisition.

  3. Sparse data approaches to enable us to leverage old and imperfect data – those collected over past years with older technologies – to unlock the statistical power of large pre-existing biobanks and real-world datasets.

  4. Automated analytics pipelines to maximize value from the data we collect and minimize labor-intensive computational biologist input, ideally with the power to push insights to researchers in real time.

  5. Defining mechanistic endotypes: A deep molecular understanding of an immune-mediated disease and the ability to subdivide it into mechanistic endotypes is critical to determining the right medication to target the right underlying factor of disease based on the patient’s mechanistic endotype.

Collaboration is key to success
At Janssen, we are relentlessly focused on the human impact of our work. Our goal is to deliver transformational treatments that improve the lives of the tens of millions of people suffering with immune-mediated diseases, both by discovering and developing a new generation of molecules, and by finding new ways to target existing medicines more precisely to the patients who will benefit most from them. We are achieving this through investments in research, technology, and collaborations, and a strong pipeline.

We are investing in precision medicine with urgency, which we believe reflects an enlightened commercial reality in which patients and their doctors will demand differentiated therapies tailored to individual patients. We have substantial biobank and data resources from decades of immunology clinical development and expansive end-to-end clinical trial expertise, plus a global footprint with which we can deploy novel approaches and maximize their impact.

We know that for precision medicine to be successful in fighting immune-mediated diseases, pharma, biotech, technology, and contract research organization communities must work together to find solutions. In this spirit, we seek partners and entrepreneurs with potentially transformative solutions to advance precision medicine approaches in autoimmune disease. Entrepreneurs can also apply for the chance to receive grant funding, access to the global JLABS network, and mentorship from experts across the Johnson & Johnson Family of Companies.

Interested in joining us in our mission to change the lives of patients living with immune-mediated diseases? Learn about our job opportunities here.

I spoke about precision medicine at the Johnson & Johnson Innovation Immunology Flagship event. To see my presentation Making Precision Medicine a Reality in Immune-Mediated Diseases, please click here.