Immunotherapy device could also enable clinical laboratories to receive in vivo biomarker data wirelessly
Researchers from Rice University in Houston and seven other states in the US are working on a new oncotherapy sense-and-respond implant that could dramatically improve cancer outcomes. Called Targeted Hybrid Oncotherapeutic Regulation (THOR), the technology is intended primarily for the delivery of therapeutic drugs by monitoring specific cancer biomarkers in vivo.
Through a $45 million federal grant from the Advanced Research Projects Agency for Health (ARPA-H), the researchers set out to develop an immunotherapy implantable device that monitors a patient’s cancer and adjusts antibody treatment dosages in real time in response to the biomarkers it measures.
It’s not a far stretch to envision future versions of the THOR platform also being used diagnostically to measure biomarker data and transmit it wirelessly to clinical laboratories and anatomic pathologists.
ARPH-A is a federal funding agency that was established in 2022 to support the development of high-impact research to drive biomedical and health breakthroughs. THOR is the second program to receive funding under its inaugural Open Broad Agency Announcement solicitation for research proposals.
“By integrating a self-regulated circuit, the THOR technology can adjust the dose of immunotherapy reagents based on a patient’s responses,” said Weiyi Peng, MD, PhD (above), Assistant Professor of Biology and Biochemistry at the University of Houston and co-principal investigator on the research, in a UH press release. “With this new feature, THOR is expected to achieve better efficacy and minimize immune-related toxicity. We hope this personalized immunotherapy will revolutionize treatments for patients with peritoneal cancers that affect the liver, lungs, and other organs.” If anatomic pathologists and clinical laboratories could receive biometric data from the THOR device, that would be a boon to cancer diagnostics. (Photo copyright: University of Houston.)
Antibody Therapy on Demand
Omid Veiseh, PhD, Associate Professor of Bioengineering at Rice University and principal investigator on the project, described the THOR device as a “living drug factory” inside the body. The device is a rod-like gadget that contains onboard electronics and a wireless rechargeable battery. It is three inches long and has a miniaturized bioreactor that contains human epithelial cells that have been engineered to produce immune modulating therapies.
“Instead of tethering patients to hospital beds, IV bags, and external monitors, we’ll use a minimally invasive procedure to implant a small device that continuously monitors their cancer and adjusts their immunotherapy dose in real time,” said Veiseh in a Rice University press release. “This kind of ‘closed-loop therapy’ has been used for managing diabetes, where you have a glucose monitor that continuously talks to an insulin pump.
But for cancer immunotherapy, it’s revolutionary.”
The team believes the THOR device will have the ability to monitor biomarkers and produce an antibody on demand that will trigger the immune system to fight cancer locally. They hope the sensor within THOR will be able to monitor biomarkers of toxicity for the purpose of fine-tuning therapies to a patient immediately in response to signals from a tumor.
“Today, cancer is treated a bit like a static disease, which it’s not,” Veiseh said. “Clinicians administer a therapy and then wait four to six weeks to do radiological measurements to see if the therapy is working. You lose quite a lot of time if it’s not the right therapy. The tumor may have evolved into a more aggressive form.”
The THOR device lasts 60 days and can be removed after that time. It is designed to educate the immune system to recognize a cancer and prevent it from recurring. If the cancer is not fully eradicated after the first implantation, the patient can be implanted with THOR again.
Use of AI in THOR Therapy
The researchers plan to spend the next two and a half years building prototypes of the THOR device, testing them in rodents, and refining the list of biomarkers to be utilized in the device. Then, they intend to take an additional year to establish protocols for the US Food and Drug Administration’s (FDA) good manufacturing practices requirements, and to test the final prototype on large animals. The researchers estimate the first human clinical trials for the device will begin in about four years.
“The first clinical trial will focus on refractory recurrent ovarian cancer, and the benefit of that is that we have an ongoing trial for ovarian cancer with our encapsulated cytokine ‘drug factory’ technology,” said Veiseh in the UH press release.
The group is starting with ovarian cancer because research in this area is lacking and it will provide the opportunity for THOR to activate the immune system against ovarian cancer, which is typically challenging to fight with immunotherapy approaches. If successful in ovarian cancer, the researchers hope to test THOR in other cancers that metastasize within the abdomen, such as:
All control and decision-making will initially be performed by a healthcare provider based on signals transmitted by THOR using a computer or smartphone. However, Veiseh sees the device ultimately being powered by artificial intelligence (AI) algorithms that could independently make therapeutic decisions.
“As we treat more and more patients [with THOR], the devices are going to learn what type of biomarker readout better predicts efficacy and toxicity and make adjustments based on that,” he predicted. “Between the information you have from the first patient versus the millionth patient you treat, the algorithm is just going to get better and better.”
Moving Forward
In addition to UH and Rice University, scientists working on the project come from several institutions, including:
More research and clinical trials are needed before THOR can be used in the clinical treatment of cancer patients. If the device reaches the commercialization stage, Veiseh plans to either form a new company or license the technology to an existing company for further development.
“We know that the further we advance it in terms of getting that human data, the more likely it is that this could then be transferred to another entity,” he told Precision Medicine Online.
Pathologists and clinical laboratories will want to monitor the progress of the THOR technology’s ability to sense changes in cancer biomarkers and deliver controlled dosages of antibiotic treatments.
Newly-defined Cardiovascular-Kidney-Metabolic Syndrome (CKM) means physicians will be in close collaboration with clinical laboratories to make accurate diagnoses
In a presidential advisory, the AHA defines a newly described systemic health disorder called Cardiovascular-Kidney-Metabolic Syndrome (CKM). The syndrome “is a systemic disorder characterized by pathophysiological interactions among metabolic risk factors, CKD (chronic kidney disease), and the cardiovascular system leading to multi-organ failure and a high rate of adverse cardiovascular outcomes.”
A CKM diagnosis, which is meant to identify patients who are at high risk of dying from heart disease, is based on a combination of risk factors, including:
weight problems,
issues with blood pressure, cholesterol, and/or blood sugar,
reduced kidney function.
CKM is a new term and doctors will be ordering medical laboratory tests associated with diagnosing patients with multiple symptoms to see if they match this diagnosis. Thus, clinical laboratory managers and pathologists will want to follow the adoption/implementation of this new recommendation.
“The advisory addresses the connections among these conditions with a particular focus on identifying people at early stages of CKM syndrome,” said Chiadi Ndumele, MD, PhD (above), Associate Professor of Medicine at Johns Hopkins University and one of the authors of the AHA paper, in a news release. “Screening for kidney and metabolic disease will help us start protective therapies earlier to most effectively prevent heart disease and best manage existing heart disease.” Clinical laboratories will play a key role in those screenings and in diagnosis of the new syndrome. (Photo copyright: Johns Hopkins University.)
Stages of CKM Syndrome
In its presidential advisory, the AHA wrote, “Cardiovascular-Kidney-Metabolic (CKM) syndrome is defined as a health disorder attributable to connections among obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), including heart failure, atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. CKM syndrome includes those at risk for CVD and those with existing CVD.”
The five stages of CKM syndrome, which the AHA provided to give a framework for patients to work towards regression of the syndrome, are:
Stage 0: No CKM risk factors. Individuals should be screened every three to five years for blood pressure, cholesterol, and blood sugar levels, and for maintaining a healthy body weight.
Stage 1: Excess body fat and/or an unhealthy distribution of body fat, such as abdominal obesity, and/or impaired glucose tolerance or prediabetes. Patients have risk factors such as weight problems or prediabetes and are encouraged to make healthy lifestyle changes and try to lose at least 5% of their body weight.
Stage 2: Metabolic risk factors and kidney disease. Includes people who already have Type 2 diabetes, high blood pressure, high triglyceride levels, and/or kidney disease. Medications that target kidney function, lower blood sugar, and which help with weight loss should be considered at this stage to prevent diseases of the heart and blood vessels or kidney failure.
Stage 3: Early cardiovascular disease without symptoms in people with metabolic risk factors or kidney disease or those at high predicted risk for cardiovascular disease. People show signs of disease in their arteries, or have heart function issues, or may have already had a stroke or heart attack or have kidney or heart failure. Medication may also be needed at this stage.
Stage 4: Symptomatic cardiovascular disease in people with excess body fat, metabolic risk factors or kidney disease. In this stage, people are categorized as with or without having kidney failure. May also have already had a heart attack, stroke or heart failure, or cardiovascular conditions such as peripheral artery disease or atrial fibrillation.
“We now have several therapies that prevent both worsening kidney disease and heart disease,” said Chiadi Ndumele, MD, PhD, Associate Professor of Medicine at Johns Hopkins University and one of the authors of the Circulation paper, in a news release. “The advisory provides guidance for healthcare professionals about how and when to use those therapies, and for the medical community and general public about the best ways to prevent and manage CKM syndrome.”
According to an AHA 2023 Statistical Update, one in three adults in the US have three or more risk factors that contribute to cardiovascular disease, metabolic disorders, or kidney disease. While CKM affects nearly every major organ in the body, it has the biggest impact on the cardiovascular system where it can affect the blood vessels, heart muscle function, the rate of fatty buildup in the arteries, electrical impulses in the heart and more.
“There is a need for fundamental changes in how we educate healthcare professionals and the public, how we organize care and how we reimburse care related to CKM syndrome,” Ndumele noted. “Key partnerships among stakeholders are needed to improve access to therapies, to support new care models, and to make it easier for people from diverse communities and circumstances to live healthier lifestyles and to achieve ideal cardiovascular health.”
New AHA Risk Calculator
In November, the AHA announced PREVENT (Predicting risk of cardiovascular disease EVENTs), a tool that doctors can use to assess a person’s risk for heart attack, stroke, and heart failure. The new risk calculator, which incorporates CKM, allows physicians to evaluate younger people as well, and examine their long-term risks for cardiovascular issues.
Doctors can use PREVENT to assess people ages 30 to 79 and predict risk for heart attack, stroke, or heart failure over 10 to 30 years.
“Longer-term estimates are important because short-term or 10-year risk in most young adults is still going to be low. We wanted to think more broadly and apply a life-course perspective,” Khan said. “Providing information on 30-year risk may reveal earlier opportunities for intervention and prevention efforts in younger people.”
According to CDC data, about 695,000 people died of heart disease in the US in 2021. That equates to one in every five deaths. Clinical pathologists will need to understand the AHA recommendations and how doctors will be ordering clinical laboratory tests to determine if a patient has CKM. Then, labs will play a role in helping doctors monitor patients to optimize health and prevent acute episodes that put patients in the hospital.
Findings could lead to deeper understanding of why we age, and to medical laboratory tests and treatments to slow or even reverse aging
Can humans control aging by keeping their genes long and balanced? Researchers at Northwestern University in Evanston, Illinois, believe it may be possible. They have unveiled a “previously unknown mechanism” behind aging that could lead to medical interventions to slow or even reverse aging, according to a Northwestern news release.
Should additional studies validate these early findings, this line of testing may become a new service clinical laboratories could offer to referring physicians and patients. It would expand the test menu with assays that deliver value in diagnosing the aging state of a patient, and which identify the parts of the transcriptome that are undergoing the most alterations that reduce lifespan.
It may also provide insights into how treatments and therapies could be implemented by physicians to address aging.
“I find it very elegant that a single, relatively concise principle seems to account for nearly all of the changes in activity of genes that happen in animals as they change,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN. Clinical laboratories involved in omics research may soon have new anti-aging diagnostic tests to perform. (Photo copyright: Amaral Lab.)
Possible ‘New Instrument’ for Biological Testing
Researchers found clues to aging in the length of genes. A gene transcript length reveals “molecular-level changes” during aging: longer genes relate to longer lifespans and shorter genes suggest shorter lives, GEN summarized.
The phenomenon the researchers uncovered—which they dubbed transcriptome imbalance—was “near universal” in the tissues they analyzed (blood, muscle, bone, and organs) from both humans and animals, Northwestern said.
According to the National Human Genome Research Institute fact sheet, a transcriptome is “a collection of all the gene readouts (aka, transcript) present in a cell” shedding light on gene activity or expression.
The Northwestern study suggests “systems-level” changes are responsible for aging—a different view than traditional biology’s approach to analyzing the effects of single genes.
“We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease,” said Luis Amaral, PhD, Senior Author of the Study and Professor of Chemical and Biological Engineering at Northwestern, in the news release.
“So, maybe we were not focused on the right thing before. Now that we have this new understanding, it’s like having a new instrument. It’s like Galileo with a telescope, looking at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently,” Amaral added.
In their Nature Aging paper, Amaral and his colleagues wrote, “We hypothesize that aging is associated with a phenomenon that affects the transcriptome in a subtle but global manner that goes unnoticed when focusing on the changes in expression of individual genes.
“We show that transcript length alone explains most transcriptional changes observed with aging in mice and humans,” they continued.
In tissues studied, older animals’ long transcripts were not as “abundant” as short transcripts, creating “imbalance.”
“Imbalance” likely prohibited the researchers’ discovery of a “specific set of genes” changing.
As animals aged, shorter genes “appeared to become more active” than longer genes.
In humans, the top 5% of genes with the shortest transcripts “included many linked to shorter life spans such as those involved in maintaining the length of telomeres.”
Conversely, the researchers’ review of the leading 5% of genes in humans with the longest transcripts found an association with long lives.
Antiaging drugs—rapamycin (aka, sirolimus) and resveratrol—were linked to an increase in long-gene transcripts.
“The changes in the activity of genes are very, very small, and these small changes involve thousands of genes. We found this change was consistent across different tissues and in different animals. We found it almost everywhere,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN.
In their paper, the Northwestern scientists noted implications for creation of healthcare interventions.
“We believe that understanding the direction of causality between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open novel research directions for antiaging interventions,” they wrote.
While more research is needed to validate its findings, the Northwestern study is compelling as it addresses a new area of transcriptome knowledge. This is another example of researchers cracking open human and animal genomes and gaining new insights into the processes supporting life.
For clinical laboratories and pathologists, diagnostic testing to reverse aging and guide the effectiveness of therapies may one day be possible—kind of like science’s take on the mythical Fountain of Youth.
Should their research result in new ways to identify and diagnose disease, doctors and clinical laboratories would do confirmatory testing and then initiate a precision medicine plan.
Dan Roden, MD, Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study, said in a VUMC news release that the findings support the growing use of genetic information in clinical care.
“The questions we asked were: How many people who had no previous indication for cardiac genetic testing had pathogenic or likely pathogenic variants, and how many of those people actually had a phenotype in the electronic health records?” he explained.
Arrhythmia More Common than Previously Thought
The VUMC researchers drew data for their reports from the eMERGE Phase III study, which investigated the feasibility of population genomic screening by sequencing 109 genes across the spectrum of Mendelian diseases—genetic diseases that are caused by a mutation in a single gene—in more than 20,000 individuals. The scientists returned variant results to the participants and used EHR and follow-up clinical data to ascertain patient phenotypes, according to a Northwestern University Feinberg School of Medicine news release.
The research team looked specifically at the 120 consortium participants that had disease-associated pathogenic or likely pathogenic (P/LP) variants in the arrhythmia-associated genes. An analysis of the EHR data showed that 0.6% of the studied population had a variant that increases risk for potentially life-threatening arrhythmia, and that there was overrepresentation of arrhythmia phenotypes among patients, the VUMC news release noted.
The research team returned results to 54 participants and, with clinical follow-up, made 19 diagnoses (primarily long-QT syndrome) of inherited arrhythmia syndromes. Twelve of those 19 diagnoses were made only after variant results were returned, the study’s authors wrote.
Carlos G. Vanoye, PhD, Research Associate Professor of Pharmacology at Northwestern University (NU), said the study suggests arrhythmia genes may be more common than previously thought.
“A person can carry a disease-causing gene variant but exhibit no obvious signs or symptoms of the disease,” he said in the NU news release. “Because the genes we studied are associated with sudden death, which may have no warning signs, discovery of a potentially life-threatening arrhythmia gene variant can prompt additional clinical work-up to determine risks and guide preventive therapies.”
“The take-home message is that 3% of people will carry a pathogenic or likely pathogenic variant in a disease-causing gene and many others will carry variants of uncertain significance,” said Dan Roden, MD (above), Senior Vice President for Personalized Medicine at VUMC and Senior Author of the Circulation study in the VUMC news release. “We can use genetic testing, electronic health record phenotypes, and in vitro technologies to evaluate and find people who have unrecognized genetic disease and save lives by making earlier diagnoses.” Clinical laboratories will play a key role in making those early diagnoses and in managing personalized medical treatment plans. (Photo copyright: Vanderbilt University.)
Variants of Uncertain Significance
According to the NU news release, the scientists determined the functional consequences of the variants of uncertain significance they found and used that data to refine the assessment of pathogenicity. In the end, they reclassified 11 of the variants: three that were likely benign and eight that were likely pathogenic.
In the JAMA Oncology study, the VUMC scientists and other researchers conducted a phenome-wide association study to find EHR phenotypes associated with variants in 23 hereditary cancer genes. According to the VUMC news release, they identified 19 new associations:
The VUMC study findings could improve disease diagnosis and management for cancer patients and help identify high-risk individuals, the researchers noted in their published report.
In an editorial published in Circulation, titled, “First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons,” the professors noted that using genomic information in the case of potentially lethal inherited arrhythmia syndromes could be “lifesaving,” but questioned the benefits of reporting such secondary findings when patients are undergoing genome sequencing for other indications such as cancer.
“The likelihood that these ‘genetic diagnoses’ are translated into clinical diagnoses have not been completely evaluated,” they wrote. “In addition to the challenge of accurately identifying disease-causing genetic variants, defining the penetrance of such variants is critical to this process, i.e., what proportion of individuals in the general population with apparently pathogenic variants will develop the associated phenotype? If penetrance is low for particular gene/phenotype combinations, the costs associated with clinical screening and the psychological effects on individuals informed that they have potentially life-threatening variants may outweigh the benefits of the few new clinical diagnoses.”
These latest studies provide further evidence of the value of big data in healthcare and offer another lesson to clinical laboratories and pathologist about the future role data streaming from clinical laboratories and pathology assays may have in the growth of personalized medicine.
New nanotechnology device is significantly faster than typical rapid detection clinical laboratory tests and can be manufactured to identify not just COVID-19 at point of care, but other viruses as well
Researchers at the University of Central Florida (UCF) announced the development of an optical sensor that uses nanotechnology to identify viruses in blood samples in seconds with an impressive 95% accuracy. This breakthrough underscores the value of continued research into technologies that create novel diagnostic tests which offer increased accuracy, faster speed to answer, and lower cost than currently available clinical laboratory testing methods.
The innovative UCF device uses nanoscale patterns of gold that reflect the signature of a virus from a blood sample. UCF researchers claim the device can determine if an individual has a specific virus with a 95% accuracy rate. Different viruses can be identified by using their DNA sequences to selectively target each virus.
According to a UCF Today article, the University of Central Florida research team’s device closely matches the accuracy of widely-used polymerase chain reaction (PCR) tests. Additionally, the UCF device provides nearly instantaneous results and has an accuracy rate that’s a marked improvement over typical rapid antigen detection tests (RADT).
Debashis Chanda, PhD (above), holds up the nanotechnology biosensor he and his team at the University of Central Florida developed that can detect viruses in a blood sample in seconds with 95% accuracy and without the need for pre-preparation of the blood sample. Chanda is professor of physics at the NanoScience Technology Center and the College of Optics and Photonics (CREOL) at UCF. Should this detection device prove effective at instantly detecting viruses at the point of care, clinical laboratories worldwide could have a major new tool in the fight against not just COVID-19, but all viral pathogens. (Photo copyright: University of Central Florida.)
Genetic Virus Detection on a Chip
“The sensitive optical sensor, along with the rapid fabrication approach used in this work, promises the translation of this promising technology to any virus detection, including COVID-19 and its mutations, with high degree of specificity and accuracy,” Debashis Chanda, PhD, told UCF Today. Chanda is professor of physics at the NanoScience Technology Center at UCF and one of the authors of the study. “Here, we demonstrated a credible technique which combines PCR-like genetic coding and optics on a chip for accurate virus detection directly from blood.”
The team tested their device using samples of the Dengue virus that causes Dengue fever, a tropical disease spread by mosquitoes. The device can detect viruses directly from blood samples without the need for sample preparation or purification. This feature enables the testing to be timely and precise, which is critical for early detection and treatment of viruses. The chip’s capability also can help reduce the spread of viruses.
No Pre-processing or Sample Preparation Needed for Multi-virus Testing
The scientists confirmed their device’s effectiveness with multiple tests using varying virus concentration levels and solution environments, including environments with the presence of non-target virus biomarkers.
“A vast majority of biosensors demonstrations in the literature utilize buffer solutions as the test matrix to contain the target analyte,” Chanda told UCF Today. “However, these approaches are not practical in real-life applications because complex biological fluids, such as blood, containing the target biomarkers are the main source for sensing and at the same time the main source of protein fouling leading to sensor failure.”
The researchers believe their device can be easily adapted to detect other viruses and are optimistic about the future of the technology.
“Although there have been previous optical biosensing demonstrations in human serum, they still require off-line complex and dedicated sample preparation performed by skilled personnel—a commodity not available in typical point-of-care applications,” said Abraham Vazquez-Guardado, PhD, a Postdoctoral Fellow at Northwestern University who worked on the study, in the UCS Today article. “This work demonstrated for the first time an integrated device which separated plasma from the blood and detects the target virus without any pre-processing with potential for near future practical usages.”
More research and additional studies are needed to develop the University of Central Florida scientists’ technology and prove its efficacy. However, should the new chip prove viable for point-of-care testing, it would give clinical laboratories and microbiologists an ability to test blood samples without any advanced preparation. Combined with the claims for the device’s remarkable accuracy, that could be a boon not only for COVID-19 testing, but for testing other types of viruses as well.
