Rising hopes for rare isotopes
Even to an untrained eye, the difference between two positron emission tomography (PET) scans of a patient could not be more stark. One image, dated from July 2016, shows the ghostly outline of his body riddled with the dark spots that indicate cancerous tumour growth. These patches take up a significant portion of the entire view, shading most of the lower pelvis region but also extending throughout the spine to the neck and head, as well as under the arms and outward from the hips.
Image courtesy C. Kratochwil, TAT-group University Hospital Heidelberg and EC-JRC Karlsruhe.
In a second image, dated just eight months later, almost all of these patches are gone, except for a two small sections in the lower chest. For Kathryn Hayashi, who has spent much of her career in the biomedical sector, the change was nothing less than shocking.
Kathryn Hayashi, President & CEO TRIUMF Innovations (image courtesy of TRIUMF)
“It’s a patient scan of someone with advanced prostate cancer that has metastasized,” she explains. “You look at it and think that person has three to six months to live at best. And there’s a scan beside it of the same patient and almost all of the cancer is gone. When I saw it my first thought was ‘is this real?’”
Hayashi is the President and CEO of TRIUMF Innovations, the commercialization arm of TRIUMF, Canada’s national particle accelerator laboratory in Vancouver. In that capacity she found the side-by-side PET images to be even more compelling because of the reason for the remarkable difference between them — an isotope of the metallic element actinium, Ac-225. When combined with an antigen that targets prostate cancer tumours, this radioactive agent demonstrates a remarkable cancer-fighting capability.
The scans that caught Hayashi’s eye pertain to a definitive paper published in the journal Prostate Cancer Therapy. It describes “compassionate use” research subjects who were otherwise in palliative care and therefore granted access to this unapproved therapeutic use of Ac-225. Nevertheless, such results have left researchers increasingly eager to explore the potential of this new approach in a set of formal clinical trials that could ultimately make this isotope part of the standard pharmacopeia for fighting cancer.
Unfortunately, it is a tall order simply finding enough Ac-225 to get started down that path. The isotope remains fairly expensive and difficult to obtain, which has made it hard for researchers to confirm even its basic physical properties, never mind its more tantalizing medical implications. In fact, actinium has typically been an unwanted by-product of other work conducted with cyclotrons or nuclear reactors to obtain versions of more widely used elements, such as radium, which have established markets for medical or industrial use.
As new research points to a potentially large market that could emerge for Ac-225, administrators responsible for the specialized technology that might supply that market are weighing their options. Operators of various types of accelerators and nuclear reactors are all considering the frontier offered by the elemental barnyard of exotic isotopes, any one of which might distinguish themselves as actinium has done. Despite the prospect of competing with some of the world’s leading scientific and industrial facilities, Hayashi suggests that few of them are as well placed to do so as TRIUMF.
“In the long run, we should be able to produce more actinium and more high quality actinium than other producers,” she says, noting that the facility’s site features the world’s largest cyclotron, which could easily ramp up the global supply. “Some of what TRIUMF does amazingly well is exploring key questions in fundamental science, like expanding our understanding of dark matter or explain what happens when neutron stars collide – all of which is very important. But to also work on something that really impacts the health and lives of everyday Canadians is something I find very motivating and is really important for TRIUMF.”
That outlook has shaped a growing proportion of TRIUMF’s activities over the past decade, starting with the 2008 “isotope crisis” spawned by a breakdown of the country’s largest research reactor in Chalk River, Ontario. When this facility shut down, it interrupted almost half of the world’s production of a key molybdenum isotope, Mo-99, which was being shipped around the world to produce a technetium isotope, Tc-99m. The latter is a workhorse of modern medical imaging, providing detailed scans that doctors use to diagnose and treat millions of cardiac and cancer patients every year.
Although the supply of Mo-99 was restored within a matter of months, the event spawned a formal review of this medical market’s heavy dependence on a 50-year-old reactor. TRIUMF joined a consortium of agencies that put forward an alternative strategy for producing Tc-99m directly from cyclotrons, a technique whose feasibility was well established decades ago. This approach posed new logistical challenges, since the isotope’s half-life is just six hours, as opposed to 66 hours for Mo-99, which could be shipped from Chalk River over vast distances and still be able to produce the desired Tc-99m using a chemical generator. Nevertheless, a network of cyclotrons at major medical centres across the country is gearing up to produce Tc-99m in close proximity to the imaging facilities that are using it.
In this way Canada intends to take nuclear out of the Tc-99m manufacturing chain, an accomplishment that has attracted the attention of observers elsewhere who are taking a hard look at how they acquire this important medical resource. In the meantime, TRIUMF has been taking its own hard look at the broader field of rare isotopes, which, as the example of Ac-225 reveals, could be poised to take off in some exciting new directions.
Paul Schaffer, Director, Life Sciences, TRIUMF (image courtesy of TRIUMF)
“TRIUMF is at a sweet spot,” says Paul Schaffer, who heads up the organization’s Life Science’s division. “With isotope production dramatically shifting, we’re still trying to keep up with the innovations of this place.”
Those innovations have justified TRIUMF’s Institute for Advanced Medical Isotopes (IAMI) – a newly proposed infrastructure initiative for the TRIUMF site. Valued at over $35M, IAMI would serve as a one-stop shop for the development of various isotopes and chemical agents that could be employed in health care. It will also build on the experience of transforming Tc-99m production to pave the way for similar products. For example, IAMI will have the capabilities to meet Health Canada’s Good Manufacturing Practices requirements, enabling more isotope production for clinical trial or commercial use.
At the same time, a complementary venture, called the Advanced Rare Isotope Laboratory (ARIEL), plans to bring even more hardware to the task of studying radioactive species. This site will be home to a new accelerator based on technology developed at TRIUMF, which promises to increase the availability of Ac-225, among many others. Schaffer points out that while the annual global production of this particular isotope is about two curies, TRIUMF has regularly been discarding as much as three curies over the course of about 10 days during certain experiments where it is among the waste products generated by other reactions. ARIEL will be dedicated to ramping up the availability of this and other isotopes that have intrigued a research community long frustrated by the scarcity of material for study.
Jens Dilling, Associate Laboratory Director, Physical Sciences, TRIUMF (image courtesy of TRIUMF)
“ARIEL is the first and only purpose-built multi-user radioactive beam facility in the world,” says Jens Dilling, TRIUMF’s Associate Laboratory Director of Physical Sciences. “It would ramp up our production from 3000 hours per year to roughly 9000 hours per year. It will unlock opportunities for materials research, medical isotopes, and also fundamental sciences.”
He adds that typical users will likely be academic investigators, but their industrial partners are bound to show up as well. Some private interests may also be willing to pay for access to the equipment, a model pioneered at the Massachusetts Institute of Technology and also practised at TRIUMF, which in 2018 marked its 50th anniversary. “After all that time, we have quite a diversified portfolio,” Dilling observes.
The ARIEL accelerator should be ready for testing by 2020, then go into full operation a few years later. Meanwhile, Schaffer points out how the world’s Ac-225 supply could readily be enhanced with a beam-line on TRIUMF’s primary cyclotron.
“When you bombard thorium-232, you make a few sister isotopes that are in the radium family – radium 224 and radium 225, which decay to form the extended family of alpha- and beta-emitting isotopes,” he explains. “Actinium is one of those daughters — or maybe the prodigal son at the moment. But there is also lead-212, bismuth-212, and bismuth-213. Those products could potentially be used in therapeutic applications as well. Those are ones we could make available simply because they’re formed in conjunction with actinium through an existing irradiation program.”
Other parts of the medical community have been clamouring for strontium, which is key to producing rubidium-82, an isotope with a half-life of just over a minute that turns out to be well suited for creating detailed images of the human heart. Similarly, gallium-68 has proved useful in creating images of rapidly changing physiological conditions, such as the growth of blood vessels within a tumour. However, this isotope is currently made with generators dependent upon another isotope, germanium-68, that has been harder to source.
“The problem is that the amount of Ge-68 to stock those generators is in short supply. It’s becoming increasingly difficult to purchase the generators; the prices are going up. And in some cases I’ve heard that they’re simply cancelling orders because they can’t keep up with the demand.”
Schaffer adds that by taking advantage of the same model that transformed Tc-99m output across the country, any currently operating cyclotron site could employ zinc targets to meet its daily gallium-68 needs directly, thereby eliminating the need to produce, package, and ship Ge-68 generators.
In this way, the hard-won lessons of guiding Canadian medical imaging from a dependence on the Chalk River reactor — which was permanently retired this spring — are giving TRIUMF an edge in a much more expansive marketplace populated by isotopes that have yet to achieve their full potential. The trail blazed by Ac-225 could set a pattern for others to follow.
“Because of the size and power of the cyclotron at TRIUMF, we have the infrastructure to produce mass quantities, enough to make this a commercial therapy,” concludes Hayashi. “We have the potential to bring this isotope to production levels that could make this a viable therapy available to patients around the world.”
Hot cell for processing actinium from irradiated targets (image courtesy of TRIUMF)
The inner chamber of TRIUMF's main cyclotron (image courtesy of TRIUMF)
Inside the vault of TRIUMF's main cyclotron (image courtesy of TRIUMF)