Prostate Cancer Lab #28: Bringing Novel Immune System Tests from Research to Clinical Use (Keith Wharton)

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 they 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 tests (gene sequencing, RNA sequencing, proteomics, spatial, and single cell analysis) in a pathology workflow leading directly to treatment guidance. Biomarkers will be identified which will select targeted treatments and predict patient outcomes. Multiple fluorescence stains will be applied to tissue and stacked to visualize the tumor microenvironment. Artificial intelligence will be applied to the images and do a better job than a pathologist at interpreting them and predicting patient progression 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 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 patients. They are not cheap. 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?

• Modeling: Testing can reveal that there are differences between cells, but we don’t know what they’re doing. It’s telling us something about the patient’s tumor 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. You also need to know 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 or cold, but the area in the middle between these extremes is where false positive and false negative diagnoses may occur, leading to errors in recommending or denying treatment, causing harm and 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 that works for lower levels of HER2, and the diagnostic needs to be 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 and have an international certification that a patient signs 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 process requires multiple steps with modular components, system lockdown standardization, strict and expensive testing on reproducibility, and robust performance. No one company can do all the tests and analyses in the workflow. Different companies have different strengths, different business models, and different pressures. And there’s no incentive to standardize. If you’re an academic doing academic research, your job is to carve a moat around you so that you 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 think you have any competitors. All the incentives for all the players are against collaboration. Pharma companies don’t agree on anything. Everybody thinks that this type of marker is better for this cell type, and then you must go to another company for something else.

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 these real-world patients from whom we can learn.