Getting Personal
By Claudia Stahl
Radiology Today
Vol. 25 No. 2 P. 12

Imaging biomarkers are improving therapy precision.

Personalized medicine (PM), also known as precision medicine, describes a wide variety of highly targeted, individualized approaches to disease treatment and management. From pharmacogenomics to radiopharmaceuticals, the ultimate goal is to achieve the best therapeutic outcome in a manner tailored to each patient.

Biomarkers play a central role in the innovation of new therapeutic approaches in PM. In nuclear medicine, theranostics, a form of personalized therapy that integrates radiotherapeutics and diagnostic imaging, is finding its way into medical centers across the country, mostly for the treatment of cancer. Theranostics uses a radioligand to simultaneously bind to target tumor markers and destroy cancer cells, facilitating precision oncology— especially for prostate, breast, and neuroendocrine cancers.

PM in Neurodegenerative Diseases
Last July, the FDA approved lecanemab (Leqembi), a monoclonal antibody, to treat early-stage Alzheimer’s disease (AD) in people who have elevated beta-amyloid in the brain, including people with AD-associated mild cognitive impairment or mild dementia. The breakthrough, which has given hope to thousands of people living with AD, supports the importance of biomarker research in AD and other dementias.

“Alzheimer’s will eventually be treated through a precision medicine and combination therapy approach that can be tailored to patients based on their individual biomarker profiles, which has proven to be successful in cancer and other diseases of chronic aging,” says Howard Fillit, MD, cofounder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF). The ADDF compiled a comprehensive research supplement on the subject, “The Biology of Aging: Leading the Next Generation of Alzheimer’s Drug Development With a Geroscience Focus,” published recently in The Journal of Prevention of Alzheimer’s Disease.

The ADDF’s consensus reflects the relatively recent embrace of biomarker research in the neurodegenerative disease space, which Sophie Cho, MD, a movement disorder neurologist and program director at the National Institute for Neurological Disorders and Stroke, says is a step in the right direction. “The field needs to continue to differentiate diseases by biomarkers in the way that oncology has for many years,” Cho says, citing arkinson’s disease (PD) as an example. “That way, we can treat the specific disease that a person has, rather than something with symptoms that look like Parkinson’s disease.”

Last October, an article in Nature Communications reported on the results of a clinical trial in which a PET tracer (ACI-12589), produced by the biopharmaceutical company AC Immune, was successful in binding to pathological alpha-synuclein in the cerebellum of patients with multiple system atrophy (MSA), an extremely difficult disease to diagnose. The trial, led by Oskar Hansson, MD, PhD, at Lund University and Skåne University Hospital, was supported by a grant from The Michael J. Fox Foundation for Parkinson’s Research.

Whereas AD and other dementias are associated with the accumulation of amyloid and tau aggregates in the brain, PD is part of a family of disorders linked to the accumulation of alphasynuclein aggregates. These “synucleinopathies” include dementia with Lewy bodies and MSA.

A rare disorder, MSA shares many symptoms with PD, such as stiffness, tremors, and problems with coordination, but it progresses more quickly. The ability to identify MSA in its early stages, in living brain tissue, and differentiate it from PD, represents a significant milestone for research, notes Francesca Capotosti, PhD, a lead researcher with AC Immune, a clinical-stage biopharmaceutical company based in Lausanne, Switzerland.

AC Immune, which develops precision medicine for neurodegenerative diseases such as AD, PD, and neuro orphan diseases, holds a proprietary library of thousands of molecules selected for their ability to cross the blood-brain barrier and bind specifically to proteins in their aggregated conformation, such as the pathological forms of beta amyloid, tau, and alpha-synuclein. Its pipeline includes PET tracers, small molecules for tau and alpha-synuclein, antibodies, and vaccines.

“We have a similar research effort underway for biofluid biomarkers, which will complement our work with PET tracers to make sure people are selected and stratified properly in clinical trials,” Capotosti says.

AC Immune will use ACI-12589 to track MSA disease progression over time, “which is something that’s lacking in the field,” and they are preparing a new PET tracer for clinical trials that has the potential to image alpha-synuclein pathology in the living brains of people with PD and AD, “where alpha-synuclein is found as a copathology in more than 50% of cases at autopsy,” Capotosti notes.

Cho agrees that a biomarker to track disease progression in MSA represents an important milestone in the management of PD-related disorders. Instead of relying on the results of a neurological exam, “we can see whether abnormal aggregates of alpha-synuclein are spreading through the brain, which may drive the progression of the disease.”

Innovation Through Collaboration
Alliances between research and industry, such as the recently announced Strategic Collaboration for Innovation in Medical Imaging and Theranostics between the Mayo Clinic in Rochester, Minnesota, and GE HealthCare, are intended to accelerate improvements in practice by bringing together research, industry, and product development at the point of patient care. The program focuses on four core areas: advanced MR technologies and techniques, theranostic agents, diagnostic and interventional ultrasound, multimodal data, AI, and digital health platforms.

For a real-world example of how it works, “We were already working with GE’s StarGuide SPECT/CT. Now GE Healthcare just purchased MIM, a software that we and many other nuclear medicine practices like for SPECT and PET imaging,” says Geoff Johnson, MD, PhD, who leads the theranostics program at the Mayo Clinic. “Now, we will be working with both MIM and GE to develop the tools to analyze SPECT imaging data and then share it with the world. ‘Here’s how this data best predicts outcome, and here’s how you analyze and process them quickly, should you have access to these kinds of scanners.’ That would be one straightforward example of that collaboration in theranostics.”

The Alzheimer’s Disease Research Centers, a program of The National Institute on Aging, funds 33 major medical institutions across the United States to accelerate advancements in the diagnosis and care of people with AD. The idea, Cho says, is to encourage collaboration and exchange of ideas. “We’re all rowing in the same boat, so we get there faster together. That’s what we promote.”

In the neurodegenerative disease space, longitudinal data is the bridge that’s needed to connect biomarker research with clinical practice. “Today, if a patient went to the clinic and tested positive for alpha-synuclein seed amplification assay, we still don’t know what that means. Will they get Parkinson’s in five years, 10 years, 20 years? Or is it a false positive? Even if it’s a true positive, there’s a chance they will not develop other signs of Parkinson’s disease,” Cho says. And if they do, “you want to be able to [pair] the marker with treatment.”

Gary Waanders, PhD, AC Immune’s head of investor relations and corporate communications, says the recent breakthroughs in AD research came as the result of being able to accurately stratify patients in clinical trials. “In the early trials, there were perhaps 20%, 30%, 40% of patients … [who] did not have the underlying pathology … so you were stacking the deck against your ability to demonstrate success … with targeted agents.”

The reverse is happening now, Waanders says. Last December, Johnson and Johnson began a clinical trial testing AC Immune’s targeted AD vaccines in people with preclinical AD based on screening for the presence of a blood biomarker, p-Tau217. “If the person presents with the right sort of profile with the blood test, then they have Tau PET. So you’re really getting a very fine characterization of patients ... and that’s going to happen in Parkinson’s and other diseases,” Waanders says. “The whole field is developing a momentum. It’s snowballing.”

— Claudia Stahl is a freelance writer based in Ambler, Pennsylvania. She specializes in writing about the health of people and the planet.

Targeted Treatment
The field of theranostics reached a breakthrough in 2022 when the FDA approved the radioligand Lutetium (Lu) 177 (Pluvicto) for treatment of metastatic, prostate-specific membrane antigen (PSMA)-positive prostate cancer. For patients who qualify, theranostics offers the possibility of living longer while living well.

“Theranostics is so specific, it doesn’t have the [negative] impact on quality of life that chemotherapy can,” says Lady Sawoszczyk, a global theranostics expert at Siemens Healthineers. Prior to her current role, Sawoszczyk managed clinical trials of Pluvicto at New York Presbyterian/ Weill Cornell Medical Center, where she witnessed remarkable therapeutic outcomes. “I was dancing in the hallways with patients who arrived in wheelchairs or hearing stories like, ‘I was able to attend my daughter’s wedding,’” she recalls. “It’s unbelievable to get to experience that.”

Geoff Johnson, MD, PhD, leads the theranostics program at the Mayo Clinic in Rochester, Minnesota, where Pluvicto is administered by IV in up to six sessions spaced six weeks apart. After each session, “We use next generation digital SPECT/CT to image the response to the therapy, so we are able to track changes in the tumors and adjust our management of the patient sooner,” Johnson says.

Response is evident after as few as two treatments, which allows the team to pivot quickly on treatment decisions. For example, “If the scans show that the cancer is progressing during treatment with Pluvicto … we might put the patient on a round of chemotherapy.” Conversely, if the tumors are in remission, “We might decide to discontinue treatment prior to the full course of therapy. That way, the patient gets the most effective therapy for their individual needs.”

Imaging provides a more complete picture of the therapeutic response than a biomarker blood test alone can. For example, “We might see that while most tumors are responding to therapy, correlating with the lower PSMA activity on the scans, others are not. In that case, we could continue to use the Pluvicto and irradiate the few tumors that are progressing.”

Currently, Pluvicto is only approved for use in metastatic patients who have already gone through chemotherapy or hormonal therapy, but clinical trials are underway that could validate its use as a first-line agent. This would spare patients from having to endure the toxic effects of these therapies.

“As a targeted therapy, the side effect profile of Pluvicto is extremely low. That makes a tremendous difference in a person’s quality of life,” Johnson says.

Growing Demand
The buzz around Pluvicto is creating a growing demand for the therapy from patients with metastatic prostate cancer. While there are a number of theranostics programs on the East and West Coasts and around Chicago, mostly at academic medical centers, people in the middle of the country are left with few options other than to travel long distances for care.

Sawoszczyk helps Siemens Healthineers customers create theranostics centers of excellence based on guidelines from the National Comprehensive Cancer Network and established best practices. With more than 70 recent radiopharmaceutical startups and several first-line therapies for prostate cancer in phase three, she expects her role will only get busier in the coming months.

“How do we get these programs into the hospitals down the street? A lot of patients are demanding these treatments, and more institutions are seeing the value,” she says. “One in eight men get prostate cancer, and now we’re seeing newer agents in the pipeline that are close to being submitted to the FDA as frontline treatments. That means that you’re going to have to perform a lot more therapies.”

Sawoszczyk assists practices of all sizes in managing everything from logistical to personnel considerations relative to theranostics. For example, “a radioisotope that degrades in the human body becomes waste if the patient cancels an appointment. In some cases, that isotope must be stored for months or even years, depending on the isotope, so choosing the right radiopharmaceuticals for your department and space is important,” Sawoszczyk says. “Do you have the necessary infrastructure?”

As theranostics involves participation from multiple staff—oncologists, radiologists, technical staff, and nursing, to name a few—Sawoszczyk advises hiring a theranostics coordinator to serve as a liaison between those departments and create a care pathway for the patient.

— CS