“Bringing Novel Immune System Tests from Research to Clinical Use”

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] Brad Power and Brian McCloskey October 5, 2022 “If we step on Starship Enterprise to the future, the diagnostics that are going to combine these (attributes) are, in essence, spatial phenomics. These (diagnostics) will combine multi-marker cell phenotypes with tissue contexts.

” – Keith Wharton “This technology is at that stage where there's a lot of promise. There's this mountain of evidence that suggests the immune system is doing something (to influence cancer), but nobody's ready to place the bets on (assay) cut-offs to generate the evidence.

” – Keith Wharton Meeting Summary Engaged cancer patients want access to new testing technologies that might help guide their treatment. These patients and diagnostic companies developing the new tests have a shared interest in accelerating adoption. But the diagnostic companies face a number of challenges, including modeling, calibration, regulation, and collaboration.

Keith Wharton, MD, PhD, FCAP, and VP, Medical Director, Ultivue, led a discussion on "Bringing Novel Immune System Tests from Research to Clinical Use". His experience in research and industry gives him a wide range of experience in seeing how new medical technologies come to market. What does the future hold for diagnostics guiding cancer treatment?

For example, how will cutting-edge technologies help cancer patients better understand their tumor microenvironment and identify drugs that will better target their cancer?

In the future, tissue images will be integrated with many diagnostic modalities (gene sequencing, RNA sequencing, proteomics, spatial transcriptomics, and single cell analysis) in a pathology workflow leading directly to treatment guidance. Biomarkers will be identified which will select which targeted treatments might work best, and predict patient outcomes.

Multiple fluorescence stains will be applied to tissue and stacked to visualize the tumor and its microenvironment. Artificial intelligence will be applied to the images and do a better job than a pathologist at interpreting them and predicting patient prognosis and drug response. What is the current state of analysis of the tumor microenvironment?

Most analysis of the tumor microenvironment (spatial analysis) is in an early stage of research. It is seldom being used to guide decisions for individual patients. Fluorescence imaging technologies (a sample is labeled and then emits a distinctive light) are being used today to find good and bad cells in retrospective analyses of cohorts of patients. With current technology, they are expensive.

Spatial analysis of the tumor microenvironment is rarely being combined with genetic targeting of drugs. What are the challenges for patients wishing to access a future vision of integrated testing?

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] ●Modeling: Testing can reveal th

tumor microenvironment is rarely being combined with genetic targeting of drugs. What are the challenges for patients wishing to access a future vision of integrated testing?

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] ●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.

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?

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] 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.

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] 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 doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

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.

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.

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] 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,

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] 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.

“Bringing Novel Immune System Tests from Research to Clinical Use” (Keith Wharton) [#28] 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.