alessandraWe sat down with Alessandra Cesano, M.D., Ph.D., Chief Medical Officer at NanoString Technologies, to discuss her perspective on the relationship between autoimmunity and immuno-oncology research.

NanoString (NS): Autoimmunity and cancer are referred to as the opposite sides of the same coin. What are some differences and similarities between these two disease areas?

Alessandra Cesano (AC): That’s a great expression, and in this case, the coin is the immune system. One way of thinking about it is that the immune system, similarly to any other system, can be overactive or underactive at times. When the system is overactive, as in the case of autoimmunity, tolerance to self is fundamentally broken, and the immune system attacks as foreign what it previously recognized as native. On the other side in the oncology setting, the immune system is underactive in its protective role against non-self. Cancer is essentially non-self but, to grow in immune-competent hosts, it needs to evade the immune system. In oncology, we are trying to pharmacologically break this tolerance to eradicate the cancer. To be honest, in my mind there are more similarities between autoimmunity and immuno-oncology than there are differences. In one case, the system has been deregulated losing tolerance for self and in the other it has been deregulated to the point of becoming tolerant to non-self. The tools used to measure these immune activities are the same. For example, a tool that lets you map immune system activity can be the same in both autoimmunity and immuno-oncology. The difference is the clinical setting and the samples related to the disease; the underlying biology investigated is the same.

NS: How do you believe autoimmune researchers will benefit from recent advances in immuno-oncology?

AC: I think that when it comes to searching for disease biomarkers, the autoimmune field is behind the immuno-oncology field. The oncology field spent a lot of time and resources identifying disease drivers and then developing drugs capable of effectively modulating such oncogenic targets. The autoimmune field has primarily focused on controlling the symptoms of the disease, therefore, trying to understand the underlying pathogenesis of the different autoimmune diseases has lagged. It’s not that understanding the pathogenesis was unimportant or undervalued, I think they simply didn’t have the tools needed. The autoimmunity field will benefit from tools that let them identify and understand both the common and specific mechanisms of the immune system hyperactivity as it pertains to disease pathogenesis. The complexity of the immune system requires tools that let the researcher look at the entire system. In oncology, before the advent of immuno-oncology, the identification of oncogenic driver mutations and the successful development of drugs interfering with these specific drivers made the field of personalized therapy relatively straightforward- the presence/absence of the mutation was measured as a predictive biomarker of the activity for a particular drug in a certain tumor setting. As the field grew into immuno-oncology, personalized medicine became more complex because to understand the interaction between immune system and cancer at the level of the single patient we need to look at the system level. We need to consider the genomic background of the patient, the genetic and epigenetic status of the tumor, as well as the effect of the environment in shaping the ultimate immune response against the tumor. I believe autoimmunity will benefit from this work done in the immuno-oncology field- the way in which biomarkers have been identified, developed and ultimately used to stratify patients.

NS: Likewise, how important will the study of autoimmune responses be for new immuno-oncology treatments?

AC: In immuno-oncology, with both checkpoint inhibitors and some adoptive cell therapies, we often observe adverse events symptomatically like autoimmune-related disease. Although clinically these inflammatory, anti-self events resemble idiopathic autoimmune diseases (which are chronic in nature) they respond well to steroid treatment and tend to disappear when the drug is discontinued (unless there has been severe tissue damage during treatment). This seems to suggest that idiopathic autoimmune diseases more likely result from an underlying chronic situation of “tolerance-break” that cannot be easily reproduced in its irreversibility but rather through the short use of immuno-oncology treatments.

NS: Where do you believe the field of autoimmunity is today, and what are some of the greatest challenges moving forward?

AC: As it becomes clearer that autoimmune diseases are heterogeneous in pathogenesis and clinical manifestations, the approach to treatment is changing. Like immuno-oncology patients, not all autoimmunity patients respond to a specific type of treatment. The treatment strategy for chronic autoimmune disease should be reevaluated in favor of looking for drivers of disease pathogenesis and not just ways to block the mediators and treat the symptoms. The search for biomarkers and drivers is heating up as the bridge between translational science researchers and clinicians continues to build. This bridge, which is so well established in the immuno-oncology field, is still under construction for autoimmunity, but it is developing rapidly. This holds a lot of promise for patients with autoimmune diseases.

NS: With hundreds of different autoimmune diseases what are the benefits for researchers to study across the diseases in a pan-autoimmune way?

AC: The immune system evolved to effectively balance its activity between stimulation and inhibition. The system is full of checks and balances that enables our body to fight off pathogens without killing us in the process from the byproducts of inflammation. The current state seems to suggest that at the basis of many autoimmune diseases is the deregulation of the activity of regulatory cells whose job is to modulate the strength and duration of the response of effector immune cells. It is likely that there are certain underlying mechanisms that are common to different idiopathic autoimmune diseases, similar to what we have learned in immuno-oncology (i.e. different target organ for AEs to same drug). As we start categorizing the multiple types of autoimmune diseases based on specific underlying alterations of the immune system, we might find common clusters of defects in the balance of the immune system that today are classified as different auto-immune diseases. For example, a subset of rheumatoid arthritis patients may share the same pathogenetic immune phenotype as a subset of patients with lupus or irritable bowel disease. The question then becomes why are the differences manifesting in the target organ? Would correcting the immune system in an established disease be enough to correct the issue? I don’t know- that’s what we want to learn; what makes the system go out of balance to create an autoimmune disease and then the subset of criteria that drive it to an organ in the body.

NS: Through genome-wide association studies the autoimmunity community has identified hundreds of disease-associated genes. What do you believe would be some important next steps for research to investigate with respect to the role these genes play in autoimmune disease?

AC: What in immuno-oncology we call the cancer immune cycle is actually a “non-self-immune cycle”; it’s the way in which an immune response is framed in an immune-competent host. In normal conditions the response is only framed against non-self; all the steps are part of a highly regulated process in which different cells, receptors, soluble mediators, etc… with different stimulatory or inhibitory functions play a balanced role. Building off the idea that autoimmune diseases result from a deregulated, but still standard, immune response, then all the same actors are in play—it’s the system that is out of balance. We used to just look at these actors with their immediate associations on a limited, local level. Now we can reevaluate them within the context of the entire system and check the mechanisms by which they work or don’t. The immune system is still the center of both autoimmune disease and cancer; what’s different is the antigen.

NS: What do you believe will be some of the important considerations for scientists looking to develop biomarker signatures for responders and non-responders to autoimmune treatments?

AC: There is enormous value in being able to stratify patients into groups of those who have a better or worse chance of responding positively to a treatment. In addition to being expensive these drugs and treatments have an inherent level of toxicity to the patient, so when the patient is presenting a chronic autoimmune disease we must consider the efficacy and the safety of the treatment especially with patients who are very young. Oncology has developed ways to classify patients both analytically and clinically. There’s unlikely to be just one signature but probably multiple signatures that will be critical in stratifying patients with auto-immune diseases. Classically any biomarker development starts with retrospective analysis of clinically annotated samples from previously conducted clinical trials. Unfortunately, while in oncology collecting tumor samples is part of the disease work up, the same has not been true in the autoimmunity field. Also, considering the nature and chronicity of the diseases, longitudinal samples from peripheral blood might be the more pragmatic relevant medium for biomarker discovery and development. It is important to train and validate biomarker signatures in separate sample sets to avoid over-fitting bias since typically we are looking at a greater number of variables than patients and need to avoid spurious results.

NS: Autoimmune diseases have historically used more traditional technologies such as flow cytometry, protein analysis and in recent years RNA sequencing. What advantages do you believe NanoString® will provide to this research area?

AC: The NanoString platform is well-positioned for immune profiling of different relevant tissues because it allows for multiplexing while targeting relevant biology. Autoimmunity doesn’t need a transcriptome approach—there’s enough literature to develop specific, and therefore more productive, investigations. The multiplexed assays are largely automated, high throughput, focused, standardized, and reproducible especially when compared to other technologies like flow cytometry. In addition, sample type flexibility is important in the clinical setting. The NanoString platform has shown consistent results on fresh and frozen tissue; the process automation and analysis software minimize user error and decrease the chance of bias. Together the nCounter® system and reagents provide unique tools to investigate the alterations of the immune system operating at the level of the single patient, and the effects of different pharmacological manipulations of the immune system in oncology and autoimmune diseases.

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Alessandra Cesano, M.D., Ph.D. has served as Chief Medical Officer at NanoString since July 2015. Prior to joining our company, Dr. Cesano was Chief Medical Officer at Cleave Biosciences, Inc. From 2008 to 2014, she served as Chief Medical Officer and Chief Operations Officer at Nodality, Inc., where she built and led the R&D groups, while providing the overall clinical vision for the organization. In addition, Dr. Cesano has held various management positions at Amgen, Biogen Idec and SmithKline Beecham Pharmaceuticals, where she helped to advance various oncology drugs through late stage development and FDA approvals. Dr. Cesano spent 12 years researching tumor immunology, including nine years at the Wistar Institute, an NCI Basic Cancer Center at the University of Pennsylvania. She also holds membership in several professional and scientific societies, and has been an author on over 100 research publications. Dr. Cesano received an M.D., a Board Certification in Oncology and a Ph.D. in Tumor Immunology from the University of Turin. She holds a B.S. in Science and Economics from Istituto Tecnico Commerciale.

Posted by K. Buchanan, Whip Smart Consulting, LLC