Findings could lead to new clinical laboratory tests to screen for individuals with increased risk of blood transfusion complications
Pathologists and clinical laboratory scientists who understand the complexities of blood typing from one human to another will be interested to learn that a 50 year-old mystery has brought about an exciting new discovery—a new human blood group.
British and Israeli scientists led by the UK’s NHS Blood and Transplant (NHSBT) and the University of Bristol discovered the meaning behind a missing protein molecule found in a pregnant woman five decades ago. This anomaly has now been given its own blood group identification called MAL, according to a University of Bristol new release.
“Some people can lack this blood group due to the effect of illness, but the rare inherited form of the AnWj-negative phenotype has only been found in a handful of individuals—though due to this discovery it will now be easier to find others in the future,” the news release notes.
This is important because receiving mismatched blood can be fatal.
“AnWj is a high-prevalence red blood cell (RBC) antigen in the ISBT 901 series. Only nine reports of anti-AnWj have been published since it was first documented in 1972,” according to a 2012 article published by the American Association of Blood Banks, now known as the Association for the Advancement of Blood and Biotherapies (AABB).
For even the small proportion of the population with this new blood group, diagnosing its presence can have a major impact while preventing unwanted harm.
“The work was difficult because the genetic cases are very rare. We would not have achieved this without exome sequencing, as the gene we identified wasn’t an obvious candidate and little is known about Mal protein in red cells,” said Louise Tilley, PhD, Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release.
“The genetic background of AnWj has been a mystery for more than 50 years, and one which I personally have been trying to resolve for almost 20 years of my career,” said Louise Tilley, PhD (above), Senior Research Scientist, IBGRL Red Cell Reference at NHS Blood and Transplant, in the news release. “It represents a huge achievement, and the culmination of a long term effort, to finally establish this new blood group system and be able to offer the best care to rare, but important, patients,” she added. Clinical laboratory scientists involved in blood banking will want to keep updated as further research into this new blood group is published. (Photo copyright: NHS Blood and Transplant.)
Unraveling the Mystery
In 1972, scientists were stumped by a pregnant woman with a blood sample that was “mysteriously missing a surface molecule found on all other known red blood cells at the time,” Science Alert reported. The AnWj antigen that was missing in that patient’s blood is present in 99.9% of human blood samples.
“Researchers found that the AnWj antigen is carried on the Mal protein. While illness can cause some people to lose the AnWj antigen, inherited cases of the AnWj-negative phenotype are extremely rare. Using whole exome sequencing on five genetically AnWj-negative individuals, researchers confirmed that, in these cases, the participants lacked the antigen due to homozygous deletions in the MAL gene,” an AABB news release stated.
The researchers named the group with the missing antigen the MAL blood group (short for Myelin and Lymphocyte Protein) which is where the antigen resides.
Genetic sequencing enabled the scientists to locate the gene when they “inserted the normal MAL gene into blood cells that were AnWj-negative. This effectively delivered the AnWj antigen to those cells,” Science Alert noted.
Mutated MAL genes result in the AnWj-negative blood type. The team discovered three patients with the blood type and no mutation, “Suggesting that sometimes blood disorders can also cause the antigen to be suppressed,” Science Alert added. The researchers also discovered that AnWj isn’t present in newborns but arrives sometime after they are born.
“Interestingly, all the AnWj-negative patients included in the study shared the same mutation. However, no other cell abnormalities or diseases were found to be associated with this mutation,” Science Alert said.
The discovery that “the Mal protein is responsible for binding AnWj antibodies” could lead to new clinical laboratory tests to screen for patients at risk from blood transfusions, AABB noted in its news release.
Facing the Challenge
Scientists had to overcome many challenges to uncover the details of this blood type. The complexity of the protein further hindered their efforts.
“MAL is a very small protein with some interesting properties which made it difficult to identify, and this meant we needed to pursue multiple lines of investigation to accumulate the proof we needed to establish this blood group system,” said Tim Satchwell, PhD, senior lecturer and cell biologist at the University of the West of England, in the University of Bristol news release.
“Resolving the genetic basis for AnWj has been one of our most challenging projects,” Nicole Thornton, head of IBGRL Red Cell Reference at NHSBT told the AABB. “There is so much work that goes into proving that a gene does actually encode a blood group antigen, but it is what we are passionate about, making these discoveries for the benefit of rare patients around the world.”
It’s hard to pinpoint how many individuals will benefit by testing for the blood group, Tilley told the BBC. Nevertheless, “the NHSBT is the last resort for about 400 patients across the world each year,” the BBC reported.
While more research needs to be done, the initial discovery is promising and may lead to new clinical laboratory tests to identify individuals who could be severely harmed should they receive the wrong blood type during a transfusion.
These advances in the battle against cancer could lead to new clinical laboratory screening tests and other diagnostics for early detection of the disease
As Dark Daily reported in part one of this story, the World Economic Forum (WEF) has identified 12 new breakthroughs in the fight against cancer that will be of interest to pathologists and clinical laboratory managers.
As we noted in part one, the WEF originally announced these breakthroughs in an article first published in May 2022 and then updated in October 2024. According to the WEF, the World Health Organization (WHO) identified cancer as a “leading cause of death globally” that “kills around 10 million people a year.”
The WEF is a non-profit organization base in Switzerland that, according to its website, “engages political, business, academic, civil society and other leaders of society to shape global, regional and industry agendas.”
Monday’s ebrief focused on four advances identified by WEF that should be of particular interest to clinical laboratory leaders. Here are the others.
Personalized Cancer Vaccines in England
The National Health Service (NHS) in England, in collaboration with the German pharmaceutical company BioNTech, has launched a program to facilitate development of personalized cancer vaccines. The NHS Cancer Vaccine Launch Pad will seek to match cancer patients with clinical trials for the vaccines. The Launch Pad will be based on messenger ribonucleic acid (mRNA) technology, which is the same technology used in many COVID-19 vaccines.
The BBC reported that these cancer vaccines are treatments, not a form of prevention. BioNTech receives a sample of a patient’s tumor and then formulates a vaccine that exposes the cancer cells to the patient’s immune system. Each vaccine is tailored for the specific mutations in the patient’s tumor.
“I think this is a new era. The science behind this makes sense,” medical oncologist Victoria Kunene, MBChB, MRCP, MSc (above), trial principal investigator from Queen Elizabeth Hospital Birmingham (QEHB) involved in an NHS program to develop personalized cancer vaccines, told the BBC. “My hope is this will become the standard of care. It makes sense that we can have something that can help patients reduce their risk of cancer recurrence.” These clinical trials could lead to new clinical laboratory screening tests for cancer vaccines. (Photo copyright: Queen Elizabeth Hospital Birmingham.)
Seven-Minute Cancer Treatment Injection
NHS England has also begun treating eligible cancer patients with under-the-skin injections of atezolizumab, an immunotherapy marketed under the brand name Tecentriq, Reuters reported. The drug is usually delivered intravenously, a procedure that can take 30 to 60 minutes. Injecting the drug takes just seven minutes, Reuters noted, saving time for patients and cancer teams.
The drug is designed to stimulate the patient’s immune system to attack cancer cells, including breast, lung, liver, and bladder cancers.
AI Advances in India
One WEF component—the Center for the Fourth Industrial Revolution (C4IR)—aims to harness emerging technologies such as artificial intelligence (AI) and virtual reality. In India, the organization says the Center is seeking to accelerate use of AI-based risk profiling to “help screen for common cancers like breast cancer, leading to early diagnosis.”
Researchers are also exploring the use of AI to “analyze X-rays to identify cancers in places where imaging experts might not be available.”
Using AI to Assess Lung Cancer Risk
Early-stage lung cancer is “notoriously hard to detect,” WEF observed. To help meet this challenge, researchers at Massachusetts Institute of Technology (MIT) developed an AI model known as Sybil that analyzes low-dose computed tomography scans to predict a patient’s risk of getting the disease within the next six years. It does so without a radiologist’s intervention, according to a press release.
Using Genomics to Identify Cancer-Causing Mutations
In what has been described as the “largest study of whole genome sequencing data,” researchers at the University of Cambridge in the UK announced they have discovered a “treasure trove” of information about possible causes of cancer.
Using data from England’s 100,000 Genomes Project, the researchers analyzed the whole genome sequences of 12,000 NHS cancer patients.
This allowed them “to detect patterns in the DNA of cancer, known as ‘mutational signatures,’ that provide clues about whether a patient has had a past exposure to environmental causes of cancer such as smoking or UV light, or has internal, cellular malfunctions,” according to a press release.
The researchers also identified 58 new mutational signatures, “suggesting that there are additional causes of cancer that we don’t yet fully understand,” the press release states.
The study appeared in April 2022 in the journal Science.
Validation of CAR-T-Cell Therapy
CAR-T-cell therapy “involves removing and genetically altering immune cells, called T cells, from cancer patients,” WEF explained. “The altered cells then produce proteins called chimeric antigen receptors (CARs), which can recognize and destroy cancer cells.”
The therapy appeared to receive validation in 2022 when researchers at the University of Pennsylvania published an article in the journal Nature noting that two early recipients of the treatment were still in remission after 12 years.
However, the US Food and Drug Administration (FDA) announced in 2023 that it was investigating reports of T-cell malignancies, including lymphoma, in patients who had received the treatment.
WEF observed that “the jury is still out as to whether the therapy is to blame but, as a precaution, the drug packaging now carries a warning.”
Breast Cancer Drug Repurposed for Prevention
England’s NHS announced in 2023 that anastrozole, a breast cancer drug, will be available to post-menopausal women to help reduce their risk of developing the disease.
“Around 289,000 women at moderate or high risk of breast cancer could be eligible for the drug, and while not all will choose to take it, it is estimated that if 25% do, around 2,000 cases of breast cancer could potentially be prevented in England, while saving the NHS around £15 million in treatment costs,” the NHS stated.
The tablet, which is off patent, has been used for many years to treat breast cancer, the NHS added. Anastrozole blocks the body’s production of the enzyme aromatase, reducing levels of the hormone estrogen.
Big Advance in Treating Cervical Cancer
In October 2024, researchers announced results from a large clinical trial demonstrating that a new approach to treating cervical cancer—one that uses currently available therapies—can reduce the risk of death by 40% and the risk of relapsing by 36%.
“This is the biggest improvement in outcome in this disease in over 20 years,” said Mary McCormack, PhD, clinical oncologist at the University College London and lead investigator in the trial.
The scientists published their findings in The Lancet.
Pathologists and clinical lab managers will want to keep track of these 12 breakthrough advancements in the diagnosis and treatment of cancer highlighted by the WEF. They will likely lead to new screening tests for the disease and could save many lives.
Is it possible that there is a connection between an individual’s gut microbiota and the ability to fight off gastrointestinal (GI) cancer? Findings from a preliminary research study performed by researchers in South Korea suggest that a link between the two may exist and that fecal microbiota transplants (FMTs) may enhance the efficacy of immunotherapies for GI cancer patients.
The proof-of-concept clinical trial, conducted at the Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea, analyzed how an FMT could help 13 patients with metastatic solid tumors that were resistant to the anti-PD-1 antibody drug known as nivolumab (Opdivo). Anti-PD-1 drugs are immunotherapies that help treat cancer by improving an individual’s immune response against cancer cells.
Four of the trial participants had gastric cancer, five had esophageal cancer, and the remaining four had hepatocellular carcinoma. The patients were given a colonoscopy to implant the FMTs. The recipients also received antibiotics to reduce the response of their existing microbiotas.
The FMT donors also had gastric cancer, esophageal cancer, or hepatocellular carcinoma. Prior to donating their fecal matter, the donors experienced complete or partial response to the anti-PD-1 drugs nivolumab or pembrolizumab (Keytruda) for at least six months after receiving initial treatments.
“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” co-senior study author Hansoo Park, MD, PhD, Assistant Professor, Biomedical Science and Engineering, Gwangju Institute of Science and Technology, told The ASCO Post. “While the connection between gut microbiota and immune response to cancer therapy has been a growing area of interest, our study provides concrete evidence and new avenues for improving treatment outcomes in a broader range of cancers,” he added. Further studies may confirm the need for microbiome testing by clinical laboratories to guide clinicians treating patients with colon cancers. (Photo copyright: Gwangju Institute of Science and Technology.)
Surprising Results
Fecal material for an FMT procedure combines donated fecal matter with a sterile saline solution which is then filtered to produce a liquid solution. That solution is then administered to the recipient via colonoscopy, upper GI endoscopy, enema, or an oral capsule. The solution may also be frozen for later use.
Upon analyzing the recipients, the scientists found that six of the patients (46.2%) who had experienced resistance to immunotherapies for their cancers, benefitted from the FMTs.
“Both donors were long-lasting, good responders to anti-PD-1 inhibitors, but because we did not yet know the causative bacteria responsible for the [FMT] response, we could not predict whether the treatment would be effective,” she added.
The researchers also determined that the presence of a bacterial strain known as Prevotella merdae helped to improve the effectiveness of the FMTs, while two strains of bacteria—Lactobacillus salivarius and Bacteroides plebeius (aka, Phocaeicola plebeius)—had a detrimental impact on the transplants.
Challenges to Widespread Adoption of FMTs
The researchers acknowledge there are challenges in widespread acceptance and use of FMTs in treating cancers but remain optimistic about the possibilities.
“Developing efficient and cost-effective methods for production and distribution is necessary for widespread adoption,” Sook Ryun Park told The ASCO Post. “Addressing these challenges through comprehensive research and careful planning will be essential for integrating FMT into the standard of care for cancer treatment.”
More research and clinical trials are needed before this use of FMTs can be utilized in clinical settings. However, the study does demonstrate that the potential benefits of FMTs may improve outcomes in patients with certain cancers. As this happens, microbiologists may gain a new role in analyzing the microbiomes of patients with gastrointestinal cancers.
“By examining the complex interactions within the microbiome, we hope to identify optimal microbial communities that can be used to enhance cancer treatment outcomes,” Hansoo Park told The ASCO Post. “This comprehensive approach will help us understand how the microbial ecosystem as a whole contributes to therapeutic success.”
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.
Using algorithmic technology designed for mapping the stars, the scientists have created an imaging/spatial location platform called AstroPath which may help oncologists develop immunotherapies that work best on specific cancers. Such a capability is key to effective precision medicine techniques.
Dark Daily has regularly pointed out that technologies developed in other fields of science will eventually be brought into anatomic pathology and clinical laboratory medicine. Use of the star-mapping technology in oncology and the diagnosis of cancer is one such example.
In “Analysis of Multispectral Imaging with the AstroPath Platform Informs Efficacy of PD-1 Blockade,” published in the journal Science, the multi-institution research team wrote, “Here, we present the AstroPath platform, an end-to-end pathology workflow with rigorous quality control for creating quantitative, spatially resolved mIF [multiplex immunofluorescence] datasets. Although the current effort focused on a six-plex mIF assay, the principles described here provide a general framework for the development of any multiplex assay with single-cell image resolution. Such approaches will vastly improve the standardization and scalability of these technologies, enabling cross-site and cross-study comparisons. This will be essential for multiplex imaging technologies to realize their potential as biomarker discovery platforms and ultimately as standard diagnostic tests for clinical therapeutic decision-making.
“Drawing from the field of astronomy, in which petabytes of imaging data are routinely analyzed across a wide spectral range, [the researchers] developed a platform for multispectral imaging of whole-tumor sections with high-fidelity single-cell resolution. The resultant AstroPath platform was used to develop a multiplex immunofluorescent assay highly predictive of responses and outcomes for melanoma patients receiving immunotherapy,” the researchers added.
Using Star Mapping Software to Fight Cancer
“The application of advanced mapping techniques from astronomy has the potential to identify predictive biomarkers that will help physicians design precise immunotherapy treatments for individual cancer patients,” said Michele Cleary, PhD, CEO of the Mark Foundation for Cancer Research, in a Johns Hopkins news release.
Although the universe we live in and the universe of a cancerous tumor may not seem related, the fact is the same visualization technology can be used to map them both.
“What should be pointed out is that astronomy is mapping the sky in three dimensions, so keeping the spatial relationships while also identify each heavenly body is the goal of these algorithms,” said Robert Michel, Publisher and Editor-in-Chief of Dark Daily and its sister publication The Dark Report.
“Both aspects of that information technology have value in surgical pathology, where the spatial relationship of different cells and cell structures is relevant and important while also having the ability to identify and characterize different types of cells and cell structures. This technology appears to also be capable of identifying multiple biomarkers,” he added.
The image above, taken from the researchers’ Science paper, illustrates the “strong parallels between multispectral analyses in astronomy and emerging multiplexing platforms for pathology.” The researchers wrote, “the next generation of tissue-based biomarkers are likely to be identified by use of large, well-curated datasets. To that end, image analysis approaches originally developed for astronomy were applied to pathology specimens to produce trillions of pixels of robust tissue imaging data and facilitate assay and atlas development.” Anatomic pathologists may be direct recipients of new cancer diagnostic tools based on the AstroPath platform. (Photo copyrights: Johns Hopkins University/Mark Foundation Center for Advanced Genomics/Bloomberg-Kimmel Institute.)
AstroPath Provides 1,000 Times the Information Content from A Single Biopsy
According to the news release, “[The researchers] characterized the immune microenvironment in melanoma biopsies by examining the immune cells in and around the cancer cells within the tumor mass and then identified a composite biomarker that includes six markers and is highly predictive of response to a specific type of an immunotherapy called Anti-PD-1 therapy.”
This is where the use of AstroPath is truly innovative. Previously, researchers could only identify those biomarkers one at a time, through a painstaking process.
“For the last 40 years, pathology analysis of cancer has examined one marker at a time, which provides limited information,” said Drew Pardoll, MD, PhD, Director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy and a Johns Hopkins professor of oncology, in the news release. “Leveraging new technology, including instrumentation to image up to 12 markers simultaneously, the AstroPath imaging algorithms provide 1,000 times the information content from a single biopsy than is currently available through routine pathology,” he added.
More information about a cancerous tumor means clinicians have more tools to combat it. Treatment becomes less about finding the right immunotherapy and more about treating it immediately.
“This facilitates precision cancer immunotherapy—identifying the unique features of each patient’s cancer to predict who will respond to a given immunotherapy, such as anti-PD-1, and who will not. In doing so, it also advances diagnostic pathology from uniparameter to multiparameter assays,” Pardoll said.
Big Data and Data Analysis Is the Future of Precision Medicine
The use of data in science is changing how researchers, clinicians, pathologists, and others provide healthcare in the modern world. When it is properly collected and analyzed, data holds the key to precision medicine’s personalized and targeted patient care.
“Big data is changing science. There are applications everywhere, from astronomy to genomics to oceanography,” said Alexander S. Szalay, PhD, Bloomberg Distinguished Professor and Professor in the Department of Computer Science at Johns Hopkins University, and Director of the Institute for Data Intensive Engineering and Science (IDIES), in the news release.
“Data-intensive scientific discovery is a new paradigm. The technical challenge we face is how to get consistent, reproducible results when you collect data at scale. AstroPath is a step towards establishing a universal standard,” he added.
Should AstroPath prove to be a clinically safe and accurate method for developing precision medicine cancer therapies, anatomic pathologists can look forward to exciting new ways to diagnose cancer and determine the best courses of treatment based on each patient’s unique medical needs.
