New Immune System Tests for Cancer: From Lab to Doctor

•Modeling: Testing can reveal that there are differences between different types of immune cells that otherwise look alike in the H&E tissue stain, but we don't know what they're doing. The stains are telling us something about the patient's tumor and immune system that needs to be understood for future therapies to be designed and to know whether they're going to work.

•Calibration: It’s hard enough to identify biomarkers which predict disease progression or drug response, but that’s not the end of the story. Once you have a potential biomarker, or measurement of one or a combination of different markers, you also need to define what the cutoff is. For example, it may be easy to identify a biomarker which helps you see the extreme cases of whether a tumor is hot (with a brisk host immune response) or cold (with the relative lack of a host immune response), but the area in the middle between these extremes is where false positive and false negative diagnoses may occur, leading to errors in either recommending or denying treatment, and potentially causing harm (and professional liability). Another example is HER2, which for a couple decades was measured as positive or negative to predict if a particular drug would be effective. Then a new drug came along (“Enhertu”) that works for lower levels of HER2, and the diagnostic needs to either be redeveloped, or at least recalibrated.

•Regulation: There are many regulators which review various aspects of new tests coming into standard clinical use. The FDA regulates the testing devices. If there's a clinical trial, IRBs must sign off on it. ISO 13485 is a quality standard for manufacturers. If a lab buys stuff from a manufacturer, they want to have good manufacturing processes (GMP) and have an international certification. The patient signs documents such as an informed consent. Typically, labs are regulated by CAP/CLIA. CMS regulates reimbursements, and you don't get reimbursed if you're not accredited. Joint commissions regulate hospitals and other health care facilities. Practitioners must have a medical license and are regulated by boards and licensed by the Federation of State Medical Boards. All of these regulatory bodies should have the same goal: they want patients to be safely treated, but they have narrow, specialized roles and responsibilities.

•Collaboration: An integrated analytical testing workflow for spatial phenomics requires multiple steps with modular components that in general are not standardized or easily interoperable. In contrast, diagnostic tests require system lockdown, standardization, strict and expensive testing on reproducibility, and robust performance. No one company, lab or manufacturer, can do all the tests and analyses, and all of their workflows are different. Different companies have different strengths, different business models, and different pressures to survive and grow. And there's no incentive to standardize. If you're an academic doing research, your job is to carve a moat around you so that your findings are novel, and nobody else does what you do. You're the world leader. It's the same thing in biotech. You need market exclusivity to enhance your business model. You don't want to have any competitors. Thus, all the incentives for all the players are against collaboration. Pharma companies pursuing a new drug target don't agree on biomarkers: one company thinks that this marker is better to identify this cell type, and then you go to another company, they think a different marker is better. Standardization of marker profiles to identify particular good or bad cell types is lacking and sorely needed to drive standardization of methods to identify them. What can be done to overcome the barriers to rapid adoption of diagnostics of the tumor microenvironment? There is a huge opportunity in real world evidence studies because the vast majority of people who get cancer don't participate in clinical trials. It's from these real world patients we have the opportunity to learn from, but we are not properly investing or studying them. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Meeting Notes The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a SUMMARY KEYWORDS tumor, technology, patients, cells, called, pathologist, lab, diagnostics, tissue, biopsy, phenotypes, cd8 cells, spatial, her2, tests, marker, stain, drug, fda, study SPEAKERS Keith (78%), Brian (17%), Rick (3%), Anonymous Caregiver (2%) Brian McCloskey: Welcome everyone to the Prostate Cancer Lab. Today we're honored to have Keith Wharton with us. Keith is the VP and medical director of Ultivue. Ultivue discovers, manufactures, and uses highly sensitive DNA barcode technology-based tissue multiplex immunofluorescence staining solutions, immuno-oncology research, and biopharma therapy development, in anatomic pathology laboratories. Keith, we're going to have to start off with a translation of that description of Ultivue. We're also going to talk about what goes on behind the scenes at companies like Ultivue in developing these new testing technologies, what's the process by which these new technologies go from “Research Use Only” to being available for clinical guidance, and how patients like us can get access to these technologies to support our clinical guidance. Keith Wharton: I consider it a privilege to speak to a group like this. I know you have tremendous personal needs. I’d like to share the experiences I've had, and the decisions I've made going through my training in the field, starting at the beginning, First some disclosures: the main one which you need to be aware of is that everything we do is research; it's not producing diagnostic procedures. I wanted to tell you a little bit about my background, before I go into what we do. I know we all have a journey through life. We are all confronted with decisions to make at various points in our life as to which way we go. I was recently thumbing through some old photographs and found a photograph I took when I worked at the NIH. This was after I started med school, and before I started a PhD, 34 years ago. I had an opportunity to work at the NIH in the Fauci lab, and you can see what he looked like back then, and what I looked like back then. This was a personal post to some Facebook friends. I look back and think, “Wow, what a real privilege it was to work in this environment with these people at this stage in history. I took a picture of the wall board. To see my name on that board, I felt like I had to made it. The person I worked with the most, Ulrich Siebenlist, passed away a couple of years ago. In his obituary, he was termed “the scientists’ scientist.” He's one of the people who solidified my love of molecular biology, reductionist approaches to biology and disease, and influenced the choices I made. A couple more personal slides around my journey, talking about the epic game of Life. We go through life, make decisions, and try to make the best decisions. I started out studying engineering. I did a lot of computer programming. That strange thing in the upper left corner is a punch card. I decided to go to med school, but really got frustrated with writing Fortran (on punch cards). I got fascinated with molecular biology and ended up, believe it or not, after working in the Fauci lab, studying fruit flies. You might think, “He's in med school and studying fruit flies? What the hell's wrong?” This is what my family was asking me. “What the hell are you doing?” It turns out that that system was the only way at that point in history you could study the function of genes in entire organisms, and then you would have some hope or promise that what you're studying in fruit flies actually works the same in mice and maybe humans. I chose to study pathology, which you can see by the picture of the old time pathologist, Quincy on TV, and I ran a mouse lab eventually. I show a toolkit because the work I chose to study at that point was before the genome was cloned. It was really foundational. There was a set of genes, and I picked one of them to study for 12 years of my life that was evolved almost a billion years ago in the history of life, and has been present in some form or another and is distributed in all animal life on the planet. Among our 18,000 to 20,000 genes, there's a subset that are really old, really critical, and have been modified in evolution to create a human versus a mouse versus a fly. These are the toolkit genes. That to me was the coolest thing to do. I felt that however you studied that it would have relevance to disease downstream. That worked for a while, but then I jumped over to the other side of the board on the right, to industry. I've been fortunate to work at drug development companies Biogen and Novartis, and at Leica, which is an anatomic pathology lab provider. I was a representative to a couple of organizations and then joined Ultivue a couple of years ago. That's my journey. As I reflect on my life in industry, I've really focused both on pathology in drugs and diagnostics. I wr wrote a book with some colleagues on drugs and diagnostics, published six or seven years ago. Another mouthful: “Molecular Histopathology and Tissue Biomarkers in Drug and Diagnostic Development.” The idea with tissue biomarkers is that the information about the disease comes from the tissue. To a pathologist that is germane and obvious, but it's not obvious to the world. This is an important part of disease diagnosis, and to work with a few dozen folks to aggregate knowledge and publish it was a real privilege. Ultivue has a mission, if you look at our name, "vue" is French for “to be seen”. It's the ultimate “to be seen”. Our mission is to develop products and services using spatial genomics and the emerging knowledge of biology to enable data-driven development of personalized cancer therapies. Not tomorrow, of course, but down the road. Our vision is to give every patient the best chance at a cure by revealing the true state of their cancer. Our vision is in the future. It's not there yet. Some fast facts: We're a spinout of Harvard's Wyss Institute. We have InSituPplex, which is a labeling technology. I'll show you some pictures of that. It has some advantages. Our primary customer right now is a pharma company that wants a custom panel made. We do all of this work in house. We have experience with lots of different protein targets, and we've made lots of panels, and we've done lots of projects. We focus on immuno-oncology. There are lots of applications of this technology to biopharma in fixed tissue analysis. I'd like to start out by showing what some might consider beautiful, but maybe a pathologist would consider ugly. This is an H&E section of a typical cancer. This is lung cancer, in which you can see an aggregate of tumor cells. Between the aggregates of tumor cells is a huge number of little blue cells and so called stroma. There's a blood vessel, and there's a hemorrhage. As a pathologist, I can look at this and see what's going on. There is tremendous complexity inside every tumor, whether it's from the prostate or any site in the body. For scale, these little blue balls are about 5 to 10 microns in diameter.