Targeted delivery of therapeutic RNAs directly to cancer cells

Tel Aviv University‘s groundbreaking technology may revolutionize the treatment of cancer and a wide range of diseases and medical conditions. In the framework of this study, the researchers were able to create a new method of transporting RNA-based drugs to a subpopulation of immune cells involved in the inflammation process, and target the disease-inflamed cell without causing damage to other cells.

The study was led by Prof. Dan Peer, a global pioneer in the development of RNA-based therapeutic delivery. He is Tel Aviv University‘s Vice President for Research and Development, head of the Center for Translational Medicine and a member of both the Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, and the Center for Nanoscience and Nanotechnology. The study was published in the prestigious scientific journal Nature Nanotechnology.

Our development actually changes the world of therapeutic antibodies. Today we flood the body with antibodies that, although selective, damage all the  that express a specific receptor, regardless of their current form. We have now taken out of the equation  that can help us, that is, uninflamed cells, and via a simple injection into the bloodstream can silence, express or edit a particular gene exclusively in the cells that are inflamed at that given moment,” explains Prof. Peer.

As part of the study, Prof. Peer and his team were able to demonstrate this groundbreaking development in animal models of inflammatory bowel diseases such as Crohn’s disease and colitis, and improve all inflammatory symptoms, without performing any manipulation on about 85% of the immune system cells. Behind the innovative development stands a simple concept, targeting to a specific receptor conformation. “On every cell envelope in the body, that is, on the , there are receptors that select which substances enter the cell,” explains Prof. Peer. “If we want to inject a drug, we have to adapt it to the specific receptors on the , otherwise it will circulate in the bloodstream and do nothing. But some of these receptors are dynamic—they change shape on the membrane according to external or internal signals. We are the first in the world to succeed in creating a drug delivery system that knows how to bind to receptors only in a certain situation, and to skip over the other identical cells, that is, to deliver the drug exclusively to cells that are currently relevant to the disease.”

Source: https://phys.org/

Junk food linked to gut inflammation

Eating a Western diet impairs the immune system in the gut in ways that could increase risk of infection and inflammatory bowel disease, according to a study from researchers at Washington University School of Medicine in St. Louis and Cleveland Clinic.

The study, in mice and people, showed that a diet high in sugar and fat causes damage to Paneth cells, immune cells in the gut that help keep inflammation in check. When Paneth cells aren’t functioning properly, the gut immune system is excessively prone to inflammation, putting people at risk of inflammatory bowel disease and undermining effective control of disease-causing microbes. The findings, published in Cell Host & Microbe, open up new approaches to regulating gut immunity by restoring normal Paneth cell function.

A tiny, 3D model of the intestines formed from anti-inflammatory cells known as Paneth cells (green and red) and other intestinal cells (blue) is seen in the image above. Researchers at Washington University School of Medicine in St. Louis and Cleveland Clinic used such models, called organoids, to understand why a Western-style diet rich in fat and sugar damages Paneth cells and disrupts the gut immune system

Inflammatory bowel disease has historically been a problem primarily in Western countries such as the U.S., but it’s becoming more common globally as more and more people adopt Western lifestyles,” said lead author Ta-Chiang Liu, MD, PhD, an associate professor of pathology & immunology at Washington University. “Our research showed that long-term consumption of a Western-style diet high in fat and sugar impairs the function of immune cells in the gut in ways that could promote inflammatory bowel disease or increase the risk of intestinal infections.”

Paneth cell impairment is a key feature of inflammatory bowel disease. For example, people with Crohn’s disease, a kind of inflammatory bowel disease characterized by abdominal pain, diarrhea, anemia and fatigue, often have Paneth cells that have stopped working.

Source: https://medicine.wustl.edu/

How to Clear Brain Plaques with Light and Oxygen to Prevent Alzheimer’s

A small, light-activated molecule recently tested in mice represents a new approach to eliminating clumps of amyloid protein found in the brains of Alzheimer’s disease patients. If perfected in humans, the technique could be used as an alternative approach to immunotherapy and used to treat other diseases caused by similar amyloids. Researchers injected the molecule directly into the brains of live mice with Alzheimer’s disease and then used a specialized probe to shine light into their brains for 30 minutes each day for one week. Chemical analysis of the mouse brain tissue showed that the treatment significantly reduced amyloid protein. Results from additional experiments using human brain samples donated by Alzheimer’s disease patients supported the possibility of future use in humans.

The importance of our study is developing this technique to target the amyloid protein to enhance clearance of it by the immune system,” said Yukiko Hori, a lecturer at the University of Tokyo and co-first author of the research recently published in Brain. The small molecule that the research team developed is known as a photo-oxygenation catalyst. It appears to treat Alzheimer’s disease via a two-step process.

First, the catalyst destabilizes the amyloid plaques. Oxygenation, or adding oxygen atoms, can make a molecule unstable by changing the chemical bonds holding it together. Laundry detergents or other cleaners known as “oxygen bleach” use a similar chemical principle. The catalyst is designed to target the folded structure of amyloid and likely works by cross-linking specific portions called histidine residues. The catalyst is inert until it is activated with near-infrared light, so in the future, researchers imagine that the catalyst could be delivered throughout the body by injection into the bloodstream and targeted to specific areas using light.

Second, the destabilized amyloid is then removed by microglia, immune cells of the brain that clear away damaged cells and debris outside healthy cells. Using mouse cells growing in a dish, researchers observed microglia engulfing oxygenated amyloid and then breaking it down in acidic compartments inside the cells. “Our catalyst binds to the amyloid-specific structure, not to a unique genetic or amino acid sequence, so this same catalyst can be applied to other amyloid depositions,” said Professor Taisuke Tomita, who led the project at the University of Tokyo.

The American Society of Clinical Oncology estimates that each year in the U.S., 4,000 people are diagnosed with diseases caused by amyloid outside of the brain, collectively known as amyloidosis. The photo-oxygenation catalyst should be capable of removing amyloid protein, regardless of when or where it formed in the body. Although some existing Alzheimer’s disease treatments can slow the formation of new amyloid plaques, eliminating existing plaques is especially important in Alzheimer’s disease because amyloid begins aggregating years before symptoms appear.

Source: https://www.u-tokyo.ac.jp/

A Cannabis Molecule Reduces Plaque, Improves Cognition in Alzheimer’s

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report. The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia (DCG) and the study’s corresponding author. There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia (MCG) investigators write in the Journal of Alzheimer’s Disease.

Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. “One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Source: https://jagwire.augusta.edu/

Blocking Cancer Cells’ Use of Sugar to Boost Immune Cells

Cancer cells and immune cells share something in common: They both love sugarSugar is an important nutrient. All cells use sugar as a vital source of energy and building blocks. For immune cells, gobbling up sugar is a good thing, since it means getting enough nutrients to grow and divide for stronger immune responses. But cancer cells use sugar for more nefarious ends. So, what happens when tumor cells and immune cells battle for access to the same supply of sugar? That’s the central question that Memorial Sloan Kettering (MSK) researchers Taha Merghoub,Jedd Wolchok, and Roberta Zappasodi explore in a new study published in the journal Nature.

Using mouse models and data from human patients, the researchers found a direct relationship between the amount of sugarspecifically glucose — that a tumor consumes and the effectiveness of immunotherapy: The more sugar the tumor consumed, the less effective the immunotherapy. The findings suggest that blocking cancer cells’ use of sugar could tip the scales in favor of immune cells, especially when they are activated by immunotherapy drugs.

If we reduce a tumor’s use of glucose, then we free up more of it for immune cells to use, which benefits the immune response,” says Dr. Merghoub, who co-led the research effort.

What we think we’ve identified is a new means to improve checkpoint blockade immunotherapy,” adds Dr. Wolchok. Immune checkpoint inhibitors release the brakes on immune cells and can provide lasting benefits for people with cancer, but they do not work for everyone. The new research may provide a way to boost their effectiveness.

Dr. Wolchok, Chief of the Immuno-Oncology Service in the Human Oncology and Pathogenesis Program at MSK, also directs the Parker Institute for Cancer Immunotherapy at MSK and co-directs the Ludwig Center for Cancer Immunotherapy at MSK.

Source: https://www.mskcc.org/

Janssen Vaccine could be Rolled Out in Europe by March 15

The European Medicines Agency (EMA) has received an application for conditional marketing authorisation (CMA) for a COVID-19 vaccine developed by Janssen-Cilag International N.V. Janssen is a subsidiary of the giant pharma-company Johnson & Johnson.

EMA’s human medicines committee (CHMP) will assess the vaccine, known as COVID-19 Vaccine Janssen, under an accelerated timetable. The Committee could issue an opinion by the middle of March 2021, provided the company’s data on the vaccine’s efficacy, safety and quality are sufficiently comprehensive and robust.

Such a short time for evaluation is only possible because EMA has already reviewed some data during a rolling review. During this phase, EMA assessed quality data and data from laboratory studies which looked at how well the vaccine triggers the production of antibodies and immune cells that target SARS-CoV-2 (the virus that causes COVID-19). The Agency also looked at clinical safety data on the viral vector used in the vaccine.

EMA is now assessing additional data on the efficacy and safety of the vaccine as well as its quality. If EMA concludes that the benefits of the vaccine outweigh its risks, it will recommend granting a CMA. The European Commission will then issue a decision on whether to grant a CMA valid in all EU and EEA Member States within days.

This is the fourth CMA application for a COVID-19 vaccine since the start of the current pandemic. It comes after EMA’s evaluation of vaccines from BioNTech/Pfizer, Moderna and AstraZeneca. These vaccines are now authorised in the EU and are among the tools Member States are using to combat COVID-19.

Source: https://www.ema.europa.eu/

Soon a Vaccine to Prevent Melanoma

A personalized “cancer vaccine” may help keep a deadly form of skin cancer from growing for years, a small new study in humans suggests. Unlike vaccines that prevent infections, such as measles and influenza, cancer vaccines are a form of immunotherapy that take down cancer cells that already exist. The vaccines train immune cells, called T cells, to better recognize cancer and target it for destruction, while sparing healthy cells in the body. For example, the new experimental vaccine works by training T cells to spot specific proteins on melanoma cells, a type of skin cancer. In the study, scientists found that the T cells continue to “remember” these proteins for at least four years after the vaccination — and they even learn to recognize more melanoma-related proteins over time.

The only way that could have happened is if there was actually killing of the tumor cells. And presumably it was the T cells induced by the vaccine that did that killing,” said study author Dr. Catherine Wu, a physician-scientist with the Dana-Farber Cancer Institute and Harvard Medical School in Boston and the Broad Institute in Cambridge, Massachusetts. That’s because, once killed, tumor cells fall apart and spill their contents; T cells then swoop in to examine these remains and log that information away for future attacks, Wu said.

While the results are promising, the new study only included eight patients, and more trials need to be conducted to pin down exactly how effective the vaccine is, she added. But as of now, the limited data hint that the vaccine triggers a persistent immune response and can help keep cancer under control, especially when combined with other immunotherapies, the authors noted. The new study, published Jan. 21 in the journal Nature Medicine, included patients with advanced melanoma who had recently undergone surgery for the cancer. The researchers took samples of the patients’ removed tumors and used them to craft personalized vaccines for each of the eight participants.

Source: https://www.realclearscience.com/

Defective immune cells make us old

T cells are supposed to defend us from pathogens, but a new mouse study suggests they may also speed aging. Blocking inflammation caused by the cells or boosting their supply of a key metabolic molecule lessened the severity of some aging-related symptoms in rodents, raising the possibility these treatments could benefit older people. The discovery is “a fantastic result directly linking metabolism, inflammation, and aging,” says immunologist Kylie Quinn of RMIT University, Bundoora, in Australia. “They’ve done a really thorough job of making sure it’s the T cells” that are causing the mice to age quickly.

Our T cells let us down as we age, becoming weaker pathogen fighters. This decline helps explain why elderly people are more susceptible to infections and less responsive to vaccines. One reason T cells falter as we get older is that mitochondria, the structures that serve as power plants inside cells, begin to malfunction. But T cells might not just reflect aging. They could also promote it. Older people have chronic inflammation throughout the body, known as inflammaging, and researchers have proposed it spurs aging. T cells may stoke this process because they release inflammation-stimulating molecules.

To test that hypothesis, immunologist María Mittelbrunn of the University Hospital 12 October’s Health Research Institute and colleagues genetically modified mice to lack a protein in the mitochondria of their T cells. This alteration forces the cells to switch to a less efficient metabolic mechanism for obtaining energy.

By the time the rodents were 7 months old, typically the prime of life for a mouse, they already appeared to be in their dotage, the team reports today in Science. Compared with typical mice, the modified rodents were slow and sluggish. They had shrunken, weak muscles and were less resistant to infections. Like many elderly people, they suffered from weakened hearts and shed much of their body fatT cells from the altered mice poured out molecules that trigger inflammation, the team found, suggesting the cells could be partially responsible for the animals’ physical deterioration. “The immune system plays a role in increasing the velocity of aging,” Mittelbrunn says.

The scientists also tested whether they could slow the aging clock. First they dosed the mice with a drug that blocks tumour necrosis factor alpha (TNF-alpha), one of the inflammation-inducing molecules that T cells unleash; the treatment increased the animals’ grip strength, improved their performance in a maze, and boosted the heart’s pumping power.

Mittelbrunn and colleagues also gave the animals a compound that raises levels of nicotinamide adenine dinucleotide (NAD), a molecule that’s vital for metabolic reactions that enable cells to extract energy from food. NAD’s cellular concentrations typically decline with age, and the researchers found that ramping it up in the mice made them more active and strengthened their hearts.

Source: https://researchbank.rmit.edu.au/
AND
https://www.sciencemag.org/

How To Uncloak Cancer Cells And Reveal Them To The Immune System

Scientists at Johns Hopkins report they have designed and successfully tested an experimental, super small package able to deliver molecular signals that tag implanted human cancer cells in mice and make them visible for destruction by the animals’ immune systems. The new method was developed, say the researchers, to deliver an immune system “uncloaking” device directly to cancer cells.

Conventional immune therapies generally focus on manipulating patients’ immune system cells to boost their cancer-killing properties or injecting drugs that do the same but often have toxic side effectsA hallmark of cancer biology is a tumor cell’s ability to essentially hide from the immune system cells whose job is to identify and destroy cancer cells. Current cellular immunotherapies, notably CAR-T, require scientists to chemically alter and enhance a patient’s own harvested immune system T-cells — an expensive and time-consuming process, say the researchers. Other weapons in the arsenal of immunotherapies are drugs, including so-called checkpoint inhibitors, which have broad effects and often lead to unwanted immune-system-associated side effects, including damage to normal tissue.

By contrast, the Johns Hopkins team sought an immune system therapy that can work like a drug but that also individually engineers a tumor and its surrounding environment to draw the immune system cells to it, says Jordan Green, Ph.D, professor of biomedical engineering at the Johns Hopkins University School of Medicine.

A microscopic image of the nanoparticles used in the study. The black scale bar is 100 nm in size
 And our process happens entirely within the body,” Green says, “requiring no external manipulation of a patient’s cells.

To develop the new system, Green and his team, including Stephany Tzeng, Ph.D., a research associate in the Department of Biomedical Engineering at Johns Hopkins, took advantage of a cancer cell’s tendency to internalize molecules from its surroundings. “Cancer cells may be easier to directly genetically manipulate because their DNA has gone haywire, they divide rapidly, and they don’t have the typical checks and balances of normal cells,” says Green.

The team created a polymer-based nanoparticle — a tiny case that slips inside cells. They guided the nanoparticles to cancer cells by injecting them directly into the animals’ tumors. “The nanoparticle method we developed is widely applicable to many solid tumors despite their variability on an individual and tumor type level,” says Green, also a member of the Johns Hopkins Kimmel Cancer Center. Once inside the cell, the water-soluble nanoparticle slowly degrades over a day. It contains a ring of DNA, called a plasmid, that does not integrate into the genome and is eventually degraded as the cancer cell divides, but it stays active long enough to alter protein production in the cell.

The additional genomic material from the plasmid makes the tumor cells produce surface proteins called 4-1BBL, which work like red flags to say, “I’m a cancer cell, activate defenses.” The plasmid also forces the cancer cells to secrete chemicals called interleukins into the space around the cells. The 4-1BBL tags and interleukins are like magnets to immune system cells, and they seek to kill the foreign-looking cancer cells.

Results of the proof-of-concept experiments were published online in the Proceedings of the National Academy of Sciences.

Source: https://www.hopkinsmedicine.org/

Personalized cancer vaccines

Therapeutic cancer vaccines were first developed 100 years ago and have remained broadly ineffective to date. Before tangible results can be achieved, two major obstacles must be overcome. Firstly, since tumor mutations are unique to each patient, cancer cell antigens must be targeted extremely precisely, which is very hard to achieve. Secondly, a safe system is needed to deliver the vaccine to the right location and achieve a strong and specific immune response.

Li Tang’s team at EPFL’s School of Engineering in Switzerland is coming up with a solution to the delivery problem. The researchers have used a polymerization technique called polycondensation to develop a prototype vaccine that can travel automatically to the desired location and activate immune cells there. The patented technique has been successfully tested in mice and is the topic of a paper appearing in ACS Central Science. Li Tang has also co-founded a startup called PepGene, with partners that are working on an algorithm for quickly and accurately predicting mutated tumor antigens. Together, the two techniques should result in a new and better cancer vaccine in the next several years.

Helping the body to defend itself

Most vaccines – against measles and tetanus for example – are preventive. Healthy individuals are inoculated with weakened or inactivated parts of a virus, which prompt their immune systems to produce antibodies. This prepares the body to defend itself against future infection.

However, the aim of a therapeutic cancer vaccine is not to prevent the disease, but to help the body defend itself against a disease that is already present. “There are various sorts of immunotherapies other than vaccines, but some patients don’t respond well to them. The vaccine could be combined with those immunotherapies to obtain the best possible immune response,” explains Li Tang. Another advantage is that vaccines should reduce the risk of relapse.

Delivering a cancer vaccine to the immune system involves various stages. First, the patient is inoculated with the vaccine subcutaneously. The vaccine will thus travel to the lymph nodes, where there are lots of immune cells. Once there, the vaccine is expected to penetrate dendritic cells, which act as a kind of alert mechanism. If the vaccine stimulates them correctly, the dendritic cells present specific antigens to cancer-fighting T-cells, a process that activates and trains the T-cells to attack them.

The procedure appears simple, but is extremely hard to put into practice. Because they are very small, the components of a vaccine tend to disperse or be absorbed in the blood stream before reaching the lymph nodes.

To overcome that obstacle, Li Tang has developed a system that chemically binds the vaccine’s parts together to form a larger entity. The new vaccine, named Polycondensate Neoepitope (PNE), consists of neoantigens (mutated antigens specific to the tumor to be attacked) and an adjuvant. When combined within a solvent, the components naturally bind together, forming an entity that is too large to be absorbed by blood vessels and that travels naturally to the lymph nodes.

Source: https://actu.epfl.ch/news/