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Advances in cellular immunotherapy that spur genetically modified T cells to attack cancer cells have revolutionized the treatment of certain blood cancers. Six such CAR-T cell therapies are approved by the Food and Drug Administration to treat certain types of leukemia, lymphoma and multiple myeloma. Still, some patients’ tumors don’t respond well to these therapies, and many patients who do well initially later see their cancers return.
Now, a new study by researchers at Washington University School of Medicine in St. Louis shows that additional treatment with an immunity boosting protein called interleukin 7 (IL-7) after an infusion of these genetically modified T cells causes the cancer-fighting CAR-T cells to grow in number and become more effective at killing tumor cells.
The mouse study — published June 13 in the journal Nature Communications — suggests promise for a phase 1 clinical trial at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. The clinical trial is investigating a long-acting genetically modified type of IL-7 in conjunction with CAR-T cells targeting CD19, a B cell antigen in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). Siteman is the coordinating center and one of four sites across the country participating in the trial.
“Many researchers are trying different strategies to enhance the function of CAR-T cells in treating blood cancers,” said senior author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine and director of the Division of Oncology. “We’re interested in IL-7 because we know it is a major driver of T cell expansion. The body makes IL-7 naturally to ramp up the number of T cells when a person gets sick, for example. When we give a long-acting type of IL-7 to tumor-bearing immunodeficient mice soon after CAR-T cell treatment, we see a dramatic expansion of these CAR-T cells greater than ten-thousandfold compared to mice not receiving IL-7. These CAR-T cells also persist longer and show dramatically increased anti-tumor activity.”
CAR-T cells are manufactured using the body’s normal T cells, either from the patient or a donor. The CAR-T cells are genetically modified to specifically target a protein on the surface of the cancer cells. The targeting helps the CAR-T cells find the cancer cells, which are masters at evading immune attack. The therapy can be highly effective, but sometimes the CAR-T cells aren’t able to expand enough to kill all of the cancer, or they become overstimulated, “exhausting” their ability to function, resulting in their loss of anti-tumor effectiveness.
With these problems in mind, the researchers — including first author Miriam Y. Kim, MD, an assistant professor of medicine, and co-senior author Matthew L. Cooper, PhD, an adjunct assistant professor of medicine — were interested in whether they could harness the body’s natural way of boosting T cell numbers to enhance the therapy. But natural IL-7 normally disappears from the body quickly. Therefore, DiPersio and his team tested a modified form of IL-7 that circulates in the body for weeks, making it much more effective at supporting the CAR-T cell expansion.
Investigating two different models of B cell lymphoma in mice, the researchers showed that mice receiving CAR-T cells and long-acting IL-7 survived almost six times longer than mice receiving CAR-T cells alone. Mice treated with CAR-T cells alone survived for about one month after therapy. All mice that received long-acting IL-7 soon after the CAR-T cell treatment were still living at the end of an experimental time frame of 175 days. Further, tumor sizes in the mice that had received CAR-T cells and IL-7 were dramatically reduced, to the point of being undetectable in the majority of mice by day 35.
“In mice that received the CAR-T cells alone, the disease is controlled briefly,” DiPersio said. “But by week three, the tumor starts to return. And by week four, they start to look like the control mice that didn’t receive any active therapy. But by adding long-acting IL-7, the numbers of CAR-T cells just explode, and those mice lived beyond the time frame we set for our experiment. Our study also suggests that it may be possible to fine-tune the expansion of the CAR-T cells by controlling the number of IL-7 doses that we give.”
Washington University research laid the groundwork for using IL-7 to boost the immune system to treat disease, including its use with CAR-T cells. In addition, Richard S. Hotchkiss, MD, a professor of anesthesiology, of medicine and of surgery, and his team have studied IL-7 for its use in stimulating T cells to fight sepsis, a life-threatening response to infection. Research from the Brain Tumor Center at Siteman also has shown promise for the use of long-acting IL-7 to enhance T cells in treating glioblastoma, an aggressive brain cancer.
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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

Researchers have successfully treated type 1 diabetes in mice using pancreatic beta-cell, target-specific, chimeric antigen-receptor (CAR) regulatory T cells (Tregs), and demonstrated the feasibility of their approach to treat the human condition according to data being presented Monday, June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Ga.
The study was led by Juan Carlos Jaume, M.D., Professor and Chief of the Division of Endocrinology, Diabetes, and Metabolism, in the Department of Medicine, and Director of the Center for Diabetes and Endocrine Research (CeDER), at the University of Toledo in Toledo, Ohio.
Historically, adoptive cell transfer therapies with CAR cytotoxic T cells have proven effective for the treatment of hematologic malignancies. Jaume and his team attempted to replicate an equally effective experimental treatment for type 1 diabetes using instead non-cytotoxic, anti-inflammatory Tregs.
“The purpose of this study was to determine if pancreatic beta-cell, target-specific, human CAR Tregs could also identify human pancreatic beta cells (target) and home to human pancreatic islets (where beta cells live) in culture as they do in mice undergoing CAR Treg treatment for T1D,” Jaume said.
The researchers drew blood one to two weeks prior to pancreas surgery, followed by a collection of a small piece of the pancreas (5 cc wedge) after the pancreas was removed for a clinically indicated reason (cancer or pancreatitis).
First, they isolated Tregs from the blood samples and expanded them in vitro. Those cells were genetically modified to express a beta-cell, target-specific CAR combined with a green fluorescence protein (GFP) marker.
Second, the researchers processed the pancreas tissue for islet separation.
Then, they co-cultured the human pancreatic islets combined with the beta-cell, target-specific CAR Tregs.
Within 24 hours, confocal microscopy demonstrated the successful migration of the GFP positive, CAR Tregs onto the pancreatic islets. What’s more, the CAR Tregs significantly proliferated while in physical contact with the pancreatic islets in the subsequent 72 hours.
“Ours is the first successful, pancreatic beta-cell, target-specific CAR-Treg treatment of T1D in a humanized mouse model that closely resembles the human disease. Based on our mice and human in-vitro data, we believe treatment with pancreatic beta-cell, target-specific, CAR-Tregs will allow for recovery and reconstitution of beta cells in human T1D patients as well,” Jaume said.
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Materials provided by The Endocrine Society. Note: Content may be edited for style and length.

A study led by the University of California, Irvine shows a strong relationship between prolonged exposure to low levels of radon and lung cancer, indicating a need for enhanced protection measures. Radon gas in the air decays into tiny radioactive particles which can damage lung cells and lead to cancer.
Findings were recently published in the online journal Environmental Health Perspectives.
“Mining operations today tend to involve lower exposures than in the past, but our study shows that these lower exposures still increase a person’s lung cancer risk. Reducing radon exposure in our workplaces and homes remains an important way to reduce lung cancer,” said David B. Richardson, Ph.D., corresponding author, UCI Program in Public Health associate dean of research and professor of environmental and occupational health.
Miners historically have had among the highest levels of workplace radon exposure, but the team also noted a wide variety of other workplaces where radon presents significant hazards, including subways, tunnels, utility service ducts, underground parking garages, phosphate fertilizer plants, and oil refineries. Residential settings also pose a threat. Concentrations are typically low but can vary widely, depending on geology, building construction, ventilation and heating.
Unlike prior studies that relied heavily upon information that was collected when radon exposures were high and poorly estimated, the international team focused on contemporary miners working in Canada, the Czech Republic, France, Germany and the U.S. Their findings show that the risk of lung cancer increases with low-level radon exposures, and particularly impacts the risk of lung cancer among young adults.
“Our study underscores the need for better protections and sets a strong foundation to build a new generation of models for developing estimates on the risk of lung cancer after low-level radon exposure, which is the primary contemporary concern,” Richardson said.
The team included health professionals and academics from the U.S., Canada, the Czech Republic, France and Germany.
This work was supported by international organizations in the U.S., France, the Czech Republic and Canada: The Centers for Disease Control and Prevention under Award Number R03 OH010946; the National Institute for Occupational Safety and Health; the CDC in association with the National Institute for Occupational Safety and Health under Award Number R21OH011452; the Institute for Radiological Protection and Nuclear Safety; the National Radiation Protection Institute; the Canadian Nuclear Safety Commission; the Ontario Ministry of Labor; and the Canadian Cancer Society.
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Materials provided by University of California – Irvine. Note: Content may be edited for style and length.

Scientists at the University of Illinois Chicago have analyzed gene expression data from more than 35,000 blood vessel cells from the lungs of mice and identified two subtypes.
One subtype, which they call immune endothelial cells, or immuneECs, preferentially expressed more genes involved in inflammation and the regulation of the immune response. The devEC subtype, for developmental endothelial cells, expressed more genes involved in cell development, like cell regeneration and proliferation.
The findings are published in the journal JCI Insight. They could lead to better treatments for lung infections, which can be dangerously exacerbated by unchecked inflammation.
The UIC team, led by Dr. Jalees Rehman, classified the subtypes by extracting lung tissue from mice engineered to express a fluorescent protein only in the blood vessel endothelial cells. Using a fluorescence cell sorter, the scientists isolated the lung endothelial cells. They then sequenced RNA from thousands of individual endothelial cells and categorized them based on their prominent gene signatures.
They found multiple groups of endothelial cells, with two dominant cell types — immuneECs and devECs — which changed over time during inflammation.
“Across our experiments, consistently we observed that the blood vessel cells of the lung seem to have these different functions and groupings, and the two predominant groups become even more distinct when responding to infection or stress,” said Rehman, UIC professor in the department of pharmacology and regenerative medicine and the department of medicine at the College of Medicine. “Importantly, we also analyzed publicly available datasets of human lungs and found similar distinct groups of endothelial cells as we had observed in the mouse lungs.”
In their experiments, Rehman and his colleagues studied cells from mice with healthy lungs and mice with lungs that were injured or fighting infections due to a bacterial toxin or influenza virus. While both subtypes were present in healthy and sick lungs, the gene expression profiles of each subtype further diverged in response to infections or injury.

Researchers from McGill University and the Max Planck Institute of Colloids and Interfaces suggests that mistletoe viscin’s ultra-stiff flexible fibres, which adhere to both skin and cartilage as well as to various synthetic materials, could have a range of applications — both biomedical and beyond.
Each mistletoe berry can produce up to two metres of a gluey thread called viscin. It allows the seeds of this parasitic plant to stick to and infect host plants. Since ancient times, mistletoe berries have been explored as treatments for everything from infertility and epilepsy to cancer. But, until now, no one has fully investigated the potential medical or technical uses of the glue itself. A recent paper from McGill University and the Max Planck Institute of Colloids and Interfaces, published in PNAS Nexus, suggests that through simple processing, viscin’s ultra-stiff flexible fibres, which adhere to both skin and cartilage as well as to various synthetic materials, could have a range of applications — both biomedical and beyond.
It is a discovery that came about almost by chance — sparked by the actions of a young girl. “I had never seen mistletoe before living in Germany,” said Matthew Harrington, a senior author on the paper, and an associate professor in the Department of Chemistry at McGill University, and the Tier 2 Canada Research Chair in Green Chemistry. “So, when my daughter was playing with a berry from a mistletoe we bought from a local Christmas market, and it started sticking to everything, I was intrigued.” This is understandable since Harrington’s research focuses on exploring materials and adhesives found in nature and adapting the underlying principles for the development of advanced bio-inspired materials.
A plant with very unusual qualities
The researchers discovered that through simple processing when wet, viscin fibres, which stick to themselves as well as to other materials, could be stretched into thin films or assembled into 3D structures. They believe that this means viscin could potentially be used as a wound sealant or skin covering. What makes the flexible viscin fibres so interesting as a material is that their ability to stick to things is fully reversible under humid conditions.
“I wore a thin film of viscin on my skin for three days to observe its adhesive qualities and was able to remove it from my fingers afterwards by simply rubbing them together,” said Nils Horbelt, a recently graduated PhD student at the Max Planck Institute, and the first author on the paper, who, according to Harrington, brought the creativity and patience of a carpenter (his former profession) to the research. “But there still remain many questions about this very unusual material.”
The researchers’ next goals are to gain a better understanding of the chemistry behind this swellable, extremely sticky material so that they can then replicate the process.
“The fact that viscin can adhere to both wood and skin or feathers, may be relevant evolutionarily speaking,” adds Harrington. “But it’s harder to explain adherence to various synthetic surfaces, such as plastics, glass and metal alloys, from an adaptive point of view. So viscin may simply represent a highly versatile adhesion chemistry, which is what makes it so interesting to explore what is going on chemically.”
Given the excellent properties of mistletoe viscin and the fact that mistletoe plants are abundant, and both biodegradable and biorenewable, these findings suggest that this remarkable plant might provide more than holiday ornamentation in the future.
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Fentanyl, a mu-opioid receptor agonist, is one of the most commonly used analgesics in the hospital and may induce long-lasting behavioral and somatosensory impairment in rodents. However, whether the use of fentanyl is associated with the development of autism is not known. An animal study led by investigators at Massachusetts General Hospital (MGH), Shanghai 10th People’s Hospital, and the University of Pennsylvania has shown that fentanyl can induce changes similar to autism-like behaviors in young male and female mice. The findings are published in the British Journal of Anaesthesia.
Research by other groups has shown that N-methyl-D-aspartate receptor dysfunction contributes to autism. Variations in Grin2a and Grin2b, the genes encoding GluN2A and GluN2B subunits of N-methyl-D-aspartate receptor, are associated with autism. In addition, the anterior cingulate cortex of the brain is affected in autism.
In this current study, the research team reported that fentanyl induces autism-like behaviors in young male and female mice via activating the mu-opioid receptor in the anterior cingulate cortex. Further, these fentanyl-induced autism-like behaviors appear partially due to the hypermethylation-mediated reduction of Grin2b expression in the anterior cingulate cortex of mice.
“Because the anterior cingulate cortex is a hub for mediating social information, we focused on the expression of Grin2b in that area,” says Yuan Shen, MD, PhD, the paper’s senior author and a professor of Psychiatry at Shanghai 10th People’s Hospital. “We found fentanyl decreased expression of Grin2b in the anterior cingulate cortex. The overexpression of Grin2b prevents fentanyl-induced autism-like behavior in the mice. These findings suggest a potential mechanism to prevent or treat the autism-like behavior,” says Shen.
The group conducted experiments using an open field test (in which a mouse can walk inside a box) and an elevated plus-maze (in which a mouse can walk on an elevated platform) to detect the anxiety and stereotyped behaviors of mice. Using a three-chamber social preference test (in which a mouse can interact with another mouse), they also assessed potential social deficits. “We used these tests because impaired social interaction, stereotyped behaviors, and anxiety are the key feature of autism-like behaviors in mice,” says Zhihao Sheng, co-first author of the paper. Sheng is a graduate student at Shanghai 10th People’s Hospital.
“However, the changes of mice in these behavioral tests do not equal autism in humans. These behavioral tests are only used to study the autism-like behaviors in mice because they can demonstrate certain features of behavior changes similar to the manifestation of autism,” says Qidong Liu, PhD, co-first author and an assistant professor at Shanghai 10th People’s Hospital.
Co-senior author Zhongcong Xie, MD, PhD, adds: “There is no current evidence that fentanyl is associated with a similar effect in humans and the outcome of the animal study is not an indication to avoid fentanyl in clinical anesthesia. However, the outcome will promote further research, including clinical investigations, to determine the potential neurobehavioral influence of opioids on brain development.” Xie is director of Basic Science Research in the MGH Department of Anesthesia, Critical Care and Pain Medicine and Henry K. Beecher Professor of Anaesthesia at Harvard Medical School.
Other authors include Chun Cheng and Mengzhu Li from Shanghai 10th People’s Hospital and Shanghai First Maternity and Infant Hospital, W. Andrew Kofke from the University of Pennsylvania, and Jed Barash, a Massachusetts neurologist.
This research was supported by the Ministry of Science and Technology of China and the National Natural Science Foundation of China.
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Researchers from Wake Forest University School of Medicine have discovered a possible new approach in treating solid tumors through the creation of a novel nanoparticle. Solid tumors are found in cancers such as breast, head and neck, and colon cancer.
In the study, Xin Ming, Ph.D., associate professor of cancer biology at Wake Forest University School of Medicine, and his team used a nanoparticle to deliver a small molecule called ARL67156 to promote an anti-tumor immune response in mouse models of colon, head and neck, and metastatic breast cancer, resulting in increased survival.
The study is published online in the journal Science Translational Medicine.
Immunotherapy has transformed cancer treatment, but unfortunately, only about 20% of patients respond to treatment.
“Most solid tumors have a poor microenvironment that can make them unresponsive to conventional cancer therapeutics, including immunotherapy,” Ming said. “But this study demonstrates that nanoparticle therapeutics are promising.”
According to Ming, the levels of adenosine triphosphate (ATP), an energy-carrying molecule, are high in tumors treated with anti-cancer therapies and quickly degraded into adenosine by a series of enzymes that are highly expressed in the tumors. The presence of adenosine in the tumor microenvironments can contribute to a poor therapeutic response. The compounds like ARL67156 are unable to enter solid tumors alone because of their poor physicochemical properties. However, the nanoparticle’s design does allow the accumulation and release of ARL67156 selectively in solid tumors.
In the study, scientists used the nanoparticle as a vehicle to deliver ARL67156, an enzyme inhibitor that prevents ATP degradation into adenosine. The nanoparticle was tested in several mouse tumor models.
“We found that the nanomedicine substantially suppressed tumor growth and resulted in prolonged survival,” Ming said.
Next, researchers tested how the nanoparticle worked in combination with an anti-PD-1 antibody, a common immunotherapy. Researchers noted that the treatment worked well and synergistically with anti-PD-1 therapy.
Finally, scientists evaluated the nanomedicine in a three-dimensional in-vitro model of tumors from patients with colon or breast cancers. Similar effects were observed — enhanced tumor cell death through anti-cancer immune response.
“Our study suggests there’s potential translation of our nanoparticle therapeutic for treating human cancers and that it might also boost the effectiveness of existing treatments,” Ming said. “These findings warrant further evaluation.”
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Materials provided by Wake Forest Baptist Medical Center. Note: Content may be edited for style and length.

Valproic acid — a drug used to treat epilepsy, migraine, and bipolar disorder — can cause birth defects when taken during pregnancy. Now, a study publishing June 14thin the open access journal PLOS Biology by Bill Keyes of the Institute of Genetics and Molecular and Cellular Biology, France, and colleagues reveals one reason why: valproic acid (VPA) puts some cells of the developing nervous system into senescence, a kind of halted state that keeps them from growing and dividing correctly.
VPA is widely used to treat a number of illnesses. However, since its initial use, there have been many thousands of cases of women taking VPA during pregnancy and subsequently giving birth to children with birth defects, including spina bifida, facial alterations, and heart malformation. In addition, about a third of exposed infants develop cognitive impairment and Autism Spectrum Disorder.
In the new study, Keyes and colleagues used both human organoids — three-dimensional clusters of human cells grown in the lab — as well as mice to study embryonic exposure to VPA. They discovered that VPA induces cellular senescence in neuroepithelial cells, the stem cells that give rise to the central nervous system. Moreover, the researchers pinpointed one particular molecule, p19Arf, as being responsible for this VPA-induced senescence. When the team used mice lacking p19Arf, VPA exposure during pregnancy no longer caused microcephaly (small head size) or changes to gene expression patterns associated with Autism Spectrum Disorder, although VPA did lead to other defects even in these mice.
The work is one of the first to associate cellular senescence with developmental defects, the authors say. “Overall, the discovery that atypical activation of senescence in the embryo can perturb development raises the intriguing possibility that it may also contribute to defects in developmental contexts beyond those we studied here.”
Muriel Rhinn, first author of the study, adds, “While cellular senescence has long been associated with aging and age-related disease, we now show that aberrant induction of senescence can also contribute to developmental defects. As valproic acid is strongly linked to cognitive defects and Autism Spectrum Disorder, this study now introduces an exciting link with senescence, supporting how additional studies are needed.”
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Materials provided by PLOS. Note: Content may be edited for style and length.

Inside the body, some seemingly harmless proteins have sinister potential. In the case of Alzheimer’s disease, the amyloid-beta (Aβ) protein, which is vital for brain growth, can become tainted and destroy cells, which leads to forgetfulness and memory loss. Proteins are neat little things that can only perform their functions if folded properly. Thus, the misfolding and deposition of amyloid beta in the brain is the main hallmark of Alzheimer’s disease.
“One of the drivers of Alzheimer’s pathogenesis is the production of soluble oligomeric Aβ, which could potentially serve as a biomarker of Alzheimer’s disease,” said Tianfu Wu, University of Houston associate professor of biomedical engineering. Oligomeric proteins are composed of several protein chains or subunits packed tightly together.
Since 1959, the fluorescent dye thioflavin-T (ThT) has been a widely used “gold standard” for selectively staining and identifying amyloid fibrils, which result from the self-assembly of proteins into those large groups. However, due to the charge and emission wavelength (less than 650 nm) of ThT, the in-vivo use is limited. In addition, ThT can detect only the fibrillar form of Aβ, but not the oligomeric forms.
That’s why a new probe for in-vivo detection of the oligomeric form of Aβ is highly desirable for the early diagnosis of Alzheimer’s disease, and that’s what Wu and collaborators have been creating. “We synthesized a near-infrared fluorescence-imaging probe to detect both soluble and insoluble Aβ. It not only binds oligomeric Aβ but also interposes self-assembly of Aβ,” reports Wu in the journal Alzheimer’s and Dementia. “This work holds great promise in the early diagnosis of Alzheimer’s and may provide an alternative way to prevent and intervene in Alzheimer’s disease and other amyloidosis.”
That couldn’t come a moment too soon. According to the Alzheimer’s Association, more than 6 million Americans are living with Alzheimer’s. By 2050, this number is projected to rise to nearly 13 million.
No real prevention and treatment of this chronic, degenerative brain disease exists; only five drugs are approved by the U.S. Food and Drug Administration to treat it, and they are all palliative. Unfortunately, these medications are not able to alleviate pathological changes or delay disease progression.
“It is notable that the lack of early and accurate diagnosis of Alzheimer’s disease and disease surveillance further hinders the development of therapeutic drugs,” said Wu. “Our hope is this new probe will help us detect the disease early and form targets for prevention and progression.”
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Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.

Dementia is one of the major causes of disability and dependency among older people worldwide, affecting thinking and behaviours as you age. But what if you could stop this degenerative disease in its tracks?
A world-first study from the University of South Australia could make this a reality as new genetic research shows a direct link between dementia and a lack of vitamin D.
Investigating the association between vitamin D, neuroimaging features, and the risk of dementia and stroke, the study found: low levels of vitamin D were associated with lower brain volumes and an increased risk of dementia and stroke genetic analyses supported a causal effect of vitamin D deficiency and dementia. in some populations as much as 17 per cent of dementia cases might be prevented by increasing everyone to normal levels of vitamin D (50 nmol/L).Dementia is a chronic or progressive syndrome that leads to deterioration in cognitive function. About 487,500 Australians live with dementia and it is the country’s second leading cause of death. Globally, more than 55 million people have dementia with 10 million new cases diagnosed every year.
Supported by the National Health and Medical Research Council, the genetic study analysed data from 294,514 participants from the UK Biobank, examining the impact of low levels of vitamin D (25 nmol/L) and the risk of dementia and stroke. Nonlinear Mendelian randomisation (MR) — a method of using measured variation in genes to examine the causal effect of a modifiable exposure on disease — were used to test for underlying causality for neuroimaging outcomes, dementia, and stroke.
Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, says the findings are important for the prevention of dementia and appreciating the need to abolish vitamin D deficiency.