Interview Questions for Michael E. Phelps, UCLA
Question 1:
Given the significant advancements in PET radiopharmaceuticals over the past decade, what do you see as the most promising areas for future development? How do you envision these new radiotracers enhancing the diagnostic capabilities and clinical utility of PET imaging?
Answer:
During the last 10 years there has been an ever-accelerating growth in academic discoveries and inventions, and in capitalization of the number of companies in Theranostics. The focus of this is integration of molecular imaging with PET to image and measure the biology of disease and phenotype disease cells throughout the body to have or not have the therapeutic protein target and to image and measure therapeutic responses. Theranostics focuses on the use of two versions of radiolabeled molecular probes. One uses the probe labeled with positron emitting radioisotopes like 18F, 68Ga and 89Zr, for the imaging assays of the protein therapeutic target, and the other for therapy where the probe is labeled with radioisotopes that emit beta or alpha particles, like 177Lu or 225Ac, to radio-ablate disease cells that have the protein target. Each of these labeled probes are injected through IV, carried throughout the body by the bloodstream and cross into tissues in search of the protein target. Because of remarkable therapeutic responses with minor and manageable side effects with the initial probes, they moved quickly through FDA approval, reimbursement and adoption worldwide. This is illustrated by the diagnostic of 68Ga-DOTATATE and the therapeutic of 177Lu-DOTATATE for neuroendocrine tumors and the corresponding combination of 68Ga-PSMA-11or [18F]PSMA and 177Lu or 225Ac-PSMA for prostate cancer.
An imaging example below illustrates this Theranostic approach:
These successes have led to a rapid expansion of molecular probes for PET imaging assays and phenotyping, and therapeutics for a wide array of protein targets and in a wide array of diseases, although continuing to expand the number of different cancers that are targeted.
Question 2:
What are principles that differentiate Theranostics from other imaging diagnosis to aid therapeutic approaches?
Answer:
A) In Theranostics, the imaging part of this diagnostic and therapeutic partnership, the PET molecular imaging probes specifically target proteins involved in the biology of diseases that are therapeutic targets, and from this, to phenotype diseased cells throughout the body to determine if patients have the therapeutic protein target or not. The same, or similar molecular probe, is used for imaging and therapy. From this, you can use the imaging probe to safely determine the time course of the tissue distribution of the probe in patients to provide the analogous information for the therapy probe, and to assay the amount (dose) of the probe on the target. You can achieve this in a safe and effective manner since the imaging version of the probe is given in trace amounts with little to no significant pharmacologic or mass effects.
B) These PET imaging probes are part of what are called biomarkers of disease that are companion diagnostics to therapeutics in the world of precision medicine. Let’s examine the importance of imaging biomarkers coupled to therapy in Theranostics to put this in perspective. To do this, let’s examine the effect of PET molecular imaging and phenotyping of disease cells in a Signal to Noise analysis, where the signal is responders to therapy and noise is the non-responders, and ask the question, “What are the relative number of patients required in therapy trials for a given outcome with % changes in responders?” In the case of 20% responders to treatment (average response in drug trials), this requires 100 patients. If the responders were increased to 40% and 80% by a biomarker patient selection approach, the relative number of patients required would be 25 and 7, respectively. This produces corresponding reductions in costs, time and the number of patients taking the risk of clinical trials without adding to the desired result. Theranostics provides a demonstration of this principle in trials that is passed on to their use in healthcare.
C) The expanding number of academic and commercial research and development programs throughout the world are focused on the development of many new Theranostic combinations of PET biomarkers and therapies in an increasing number of diseases.
D) While initial successes in Theranostics are driven by successes where the therapeutic is radio-ablation of disease cells, the principles apply not only to radioablation therapy, but also to drug and cell-based therapies, although one must keep in mind the mild and manageable side effects in the radioablation therapy. The principles of Theranostics are establishing a fundamentally new and effective example of precision medicine.
Question 3
What has been the commercial and academic responses to the growing success to the precision medicine approach of Theranostics?
Answer:
Success in academic research in Theranostics is producing investments commercially. Commercial success increases academic investments and the cycle repeats. As I mentioned, in Theranostics there is an accelerating increase in commercial capitalization and an accelerating increase in start-ups, mid-size and corporations in imaging, biotechnology, biopharma and pharma. In the last 10 years, the number of new companies in Theranostics has grown to over 50 companies on the therapeutic side of Theranostics including large pharma like Norvartis, Lilly, Bristol Myers Squibb, AstroZenca and Sanofi, and importantly, a growing number of small and mid-size companies that drive innovation and discovery and move successes to larger companies through mergers and acquisition with biopharma and pharma companies.
On the molecular imaging diagnostics and phenotyping of cells throughout the body there are many innovation-driven small, mid-size and large imaging companies like GE Healthcare and Siemens Healthineers, who are aggressively moving to Theranostics by building internal programs, partnerships and acquisitions.
Question 4:
Beyond the value of PET imaging diagnostics of the biochemistry and biology of disease and phenotyping disease cells, what are the technology advances that are occurring in PET scanners and their integration with CT and MRI?
Answer:
PET, MRI, CT and ultrasound all provide valuable information in healthcare. Each provides different information by the origin of the signals used to form their images. In this array of imaging technologies, there are advances occurring for each technology, as well as combining them into single scanners such as PET/CT and PET/MRI to combine their individual source of information in the same patient examination.
PET is a technology that uses labeled molecules to assay proteins involved in metabolism, cell signaling, gene expression, immune system functions, etc. that were originally developed by biochemists, biologists and pharmacologists to study and understand these processes in vitro in health and disease. PET transfers these assays to the in vivo setting of the only true model of human disease – patients. PET does this in safe and effective ways because the imaging probes are used in trace amounts (they are called tracers) that exert no significant pharmacologic or mass effects on the biology of the body.
PET is intrinsically a whole-body imaging technology because the tracers are injected intravenously, move throughout the body with the bloodstream and are transported or diffuse into tissues of the body to search for and engage the protein target for which they are designed. PET is also an analytical imaging technology to quantify proteins and the functions they perform.
PET is fundamentally different than CT, MRI and Ultrasound, although they all provide remarkable access to disease in the body though images. PET provides measures of the biochemistry and biology of disease as the critical information in understanding, diagnosing and treating the biology of disease, and it does this safely and effectively in patients.
Academic and commercial PET scanners are being invented to improve spatial resolution,image quality and shorten the scan time. The invention of the EXPLORER Total-Body PET/CT scanner by Simon Cherry and Ramsey Badawi at UC Davis has been commercialized by a Chinese company, United Imaging Healthcare. This system provides dramatic increases in detection efficiency, spatial resolution, short scan times, and allows the entire human body to be imaged at once. Their initial commercial system developed in 2019, and was 40 times more efficient than other commercial PET/CT scanners available at that time. The United Imaging system is now FDA-approved and can provide images of the total body in a matter of a few seconds to minutes. This has inspired GE Healthcare and Siemen Healthineers to also develop new PET/CT scanners with increased body coverage, higher efficiency and spatial resolution and shortened scan times.