Tag Archives: immune cells
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.
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.
Cancer cells and immune cells share something in common: They both love sugar. Sugar 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 sugar — specifically 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.
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.
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 effects. A 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.
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.
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.
White blood cells, which release a toxic potion of proteins to kill cancerous and virus-infected cells, are protected from any harm by the physical properties of their cell envelopes, find scientists from UCL and the Peter MacCallum Cancer Centre in Melbourne. Until now, it has been a mystery to scientists how these white blood cells – called cytotoxic lymphocytes – avoid being killed by their own actions and the discovery could help explain why some tumours are more resistant than others to recently developed cancer immunotherapies.
The research, published in Nature Communications, highlights the role of the physical properties of the white blood cell envelope, namely the molecular order and electric charge, in providing such protection.
“Cytotoxic lymphocytes, or white blood cells, rid the body of disease by punching holes in rogue cells and by injecting poisonous enzymes inside. Remarkably, they can do this many times in a row, without harming themselves. We now know what effectively prevents these white blood cells from committing suicide every time they kill one of their targets,” according to Professor Bart Hoogenboom (London Centre for Nanotechnology, UCL Physics & Astronomy and UCL Structural & Molecular Biology), co-author of the study.
The scientists made the discovery by studying perforin, which is the protein responsible for the hole-punching. They found that perforin’s attachment to the cell surface strongly depends on the order and packing of the molecules – so-called lipids – in the membrane that surrounds and protects the white blood cells.
For the first time in the United States, a gene editing tool has been used to treat advanced cancer in three patients and showed promising early results in a pilot phase 1 clinical trial. So far the treatment appears safe, and more results are expected soon. To develop a safer and more effective treatment for cancer patients, scientists from the University of Pennsylvania, the Parker Institute for Cancer Immunotherapy in San Francisco and Tmunity Therapeutics, a biotech company in Philadelphia, developed an advanced version of immunotherapy. In this treatment, a patient’s own immune cells are removed from the body, trained to recognize specific cancer cells and then finally injected back into the patient where they multiply and destroy them.
Unlike chemotherapy or radiation therapy, which directly kills cancer cells, immunotherapy activates the body’s own immune system to do the work. This team used a gene editing tool called CRISPR to alter immune cells, turning them into trained soldiers to locate and kill cancer cells. By using this technique, the team hoped to develop a more effective form of immunotherapy with minimal side effects.
Better CRISPR-based gene editors for the diagnosis and treatment of cancer and other disorders, . combining chemistry, biology and nanotechnology, are used to engineer, control and deliver gene editing tools more efficiently and precisely.
The first step in making these tumor-killing cells used in the cancer drug trial was to isolate the T-cells – a type of white blood cells that fights pathogens and cancer cells – from the blood of the cancer patients. Two patients with advanced multiple myeloma and one patient with myxoid/round cell liposarcomav were enrolled for this study.
To arm the T-cells and bolster their tumor-fighting skills without harming normal cells, scientists genetically engineered the T-cells – disabling three genes and adding one gene – before returning them to the patients.
The first two of these deleted genes encode T-cell receptors, which are proteins found on the surface of the T-cells that can recognize and bind specific molecules, known as antigens, on cancer cells. When these engineered T-cells bind to these antigens, it allows them to attack and directly kill the cancer cells. But the problem is that a single T-cell can recognize multiple different antigens in the body, making them less focused on finding the cancer cells. By eliminating these two genes, the T-cells are less likely to attack the wrong target or the host, a phenomenon called autoimmunity, In addition, they disrupted a third gene, called programmed cell death protein 1, which slows down the immune response. Disabling the programmed cell death protein 1 gene improves the efficiency of T-cells.
The final step in the transformation of these cells was adding a gene which produces a new T-cell receptor that recognizes and grabs onto a specific marker on the cancer cells called NY-ESO-1. With three genes deleted and one added, the T-cells are now ready to fight cancer.