Cancer-killing virus alerts immune system

A new UC San Francisco study has shown that a cancer-killing ("oncolytic") virus currently in clinical trials may function as a cancer vaccine-in addition to killing some cancer cells directly, the virus alerts the immune system to the presence of a tumor, triggering a powerful, widespread immune response that kills cancer cells far outside the virus-infected region.

Using novel approaches to examine exactly how oncolytic viruses attack tumors, issue of Cancer Research provided surprising insights about how a viral infection can cooperate with the immune system to attack cancer cells. The study highlights an opportunity to combine this form of therapy with cancer immunotherapy drugs such as checkpoint inhibitors, which unleash the immune system's full cancer-fighting power.

The idea that viruses could fight cancer goes back to the early 20th century, when doctors noted that cancer patients sometimes experienced dramatic remission after getting viral infections. Researchers have been developing oncolytic viruses since the 1980s, but following the U.S. Food and Drug Administration's 2015 approval of Amgen's Imlygic (T-Vec) as the first oncolytic viral therapy in the U.S., such viruses have become a closely watched area of therapeutic development.

Viruses appear capable of attacking tumors in a number of different ways by directly infecting them, by releasing tumor proteins that trigger a broad immune response against the cancer, and by damaging the blood supply tumors need to survive. To better understand the underlying mechanisms of these viral therapies, a collaboration was forged between UCSF vascular researcher Donald McDonald, MD, Ph.D., and researchers at San Francisco-based biotech SillaJen Biotherapeutics Inc. (formerly Jennerex Biotherapeutics, Inc.)

SillaJen is developing an oncolytic viral therapy called Pexa-Vec, currently in phase III and phase Ib/II clinical trials for use against primary liver and colorectal cancers, respectively. Pexa-Vec is an engineered virus based on the harmless vaccinia cowpox virus, also the basis for the original smallpox vaccine. Early observations suggesting that the virus might attack cancer in part by damaging blood vessels that feed tumor growth.

To study how the modified virus attacks tumors, researchers in the McDonald lab injected it intravenously into mice genetically modified to develop neuroendocrine pancreatic cancer. They found that the virus failed to infect healthy organs or make the animals ill, but succeeded in infecting blood vessels within tumors. These initial infections caused the vessels to leak and expose the tumor cells to the virus. In these experiments, the virus managed to infect and destroy only a small proportion of tumor cells directly, the researchers found, but within five days of the initial infection, the rest of the tumor began to be killed by a powerful immune reaction.

At first small spots of the tumor were infected, but then most of the tumor started to die. The researchers found that by killing some tumor cells directly, the viral infection exposed tumor proteins that could be detected by the immune system, triggering an immune attack on the rest of the tumor. The researchers demonstrated this by temporarily getting rid of the immune system's cancer-killing cells, called CD8+ or cytotoxic T cells, and showing that without these cells, the virus killed only the initial five percent of cancer cells.

When the researchers examined the tumors, they discovered that the second drug acted by making the immune system hyper-alert to tumor proteins released by the viral infection, rather than through effects on tumor blood vessels. This finding suggests that pairing Pexa-Vec's ability to awaken the immune system to previously ignored signs of cancer with the newest generation of checkpoint inhibitors, which act by unleashing the immune system's full force, might be an extremely potent combination therapy.
           haleplushearty.blogspot.com

Immune system may prevents MRSA infection

Researchers at Johns Hopkins, the University of California, Davis, and the National Institute of Allergy and Infectious Diseases have discovered how the immune system might protect a person from recurrent bacterial skin infections caused by Staphylococcus aureus (staph). "There's a huge, unmet clinical need for new approaches against staph skin infections because of declining antibiotic development and rising drug resistance," says Lloyd Miller, M.D., Ph.D., associate professor of dermatology at the Johns Hopkins University School of Medicine.

Staph is a common bacterium and the most common cause of skin infections in people. Additionally, multidrug resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), are causing severe skin infections in healthy people outside of hospitals. And once you've had an infection, the recurrence rate is 50 percent within six months. Staph can also spread from the skin and cause invasive and life-threatening infections such as sepsis, osteomyelitis and pneumonia.

Using mice with defective immune systems, research team found that after an initial exposure of the skin to staph, they were surprisingly protected against a second skin exposure with the same bacteria. After testing for antibodies and other usual suspects of the immune system against this infection, it was not clear what immune response was protecting the mice. The researchers then tested a drug FDA-approved for treatment of multiple sclerosis, which acts by preventing certain immune cells from leaving lymph nodes for sites of inflammation.

That genetic sequencing data revealed that specific cells substantially multiplied after the initial infection, then moved to the infection site and provided protection against the second infection. These so-called gamma delta T cells account for less than 1 percent of all the cells in the lymph node prior to infection. After infection, they accounted for more than 20 percent.

Working with collaborators from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, the researchers tested blood from healthy individuals and people with a rare immune disorder that makes them highly susceptible to staph skin infections. Half of people with the disorder die by age 10, but if they survive to adulthood they somehow overcome their susceptibility to staph infections.

In blood samples from these patients, the researchers found an increase in the percentage of gamma delta T cells, similar to what they observed in mice, which remained stable over years. The findings and especially gamma delta T cells may be targeted for developing new therapies or a vaccine against staph skin infections.

         haleplushearty.blogspot.com 

How viruses affect the immune system

Fighting infections depends on bodies' capacity to quickly recognize infected cells and destroy them, a job done by a class of immune cells known as CD8+ T cells. These soldiers get some of their orders from chemical mediators known as cytokines that make them more or less responsive to outside threats. In most cases, CD8+ T cells quickly recognize and destroy infected cells to prevent the infection from spreading.

When it comes to viruses that lead to chronic infection, immune cells receive the wrong set of marching orders, which makes them less responsive," says Martin Richer, an assistant professor at McGill's Department of Microbiology & Immunology and senior author of the study. The research, conducted in Richer's lab by graduate student Logan Smith, revealed that certain viruses persist by driving the production of a cytokine that leads to modification of glycoproteins on the surface of the CD8+ T cells, making the cells less functional.

That maneuver creates time for the pathogen to outpace the immune response and establish a chronic infection. Importantly, this pathway can be targeted to restore some functionality to the T cells and enhance the capacity to control infection. The discovery of this regulatory pathway could help identify new therapeutic targets for a variety of diseases.
         haleplushearty.blogspot.com

Artificial molecules boost cancer therapy

Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. Immunotherapies are breakthrough treatments that stimulate the patient's immune cells to attack the tumor through the recognition of tumor antigens.

Dendritic cells are specialized immune cells whose role is to capture antigens from foreign bodies and present them to the immune system's killer T cells, which will then attack and destroy the invaders. For the vaccine, dendritic cells are taken out of the patient, "force-fed" with tumor antigens, and finally re-injected back into the patient. The idea is to facilitate the ability of the dendritic cells to prime killer T cells against the tumor, which is notoriously skilled in concealing itself from the patient's immune system.

Dendritic cell vaccines have achieved some clinical success but not without several limitations. For example, the tumor antigens used to "feed" the dendritic cells are generally not taken from the patient's tumor but from lab-grown cancer cells that are only partially similar to those of the patient. This can limit the power of the vaccine because its tumor antigens may differ from those of the patient's tumor, meaning that the killer T cells would not be properly activated to recognize and attack the tumor.

A group of researchers led by Michele De Palma at EPFL have now created artificial receptors called EVIR (extracellular vesicle-internalizing receptors), which enable the dendritic cells in the vaccine to selectively and efficiently capture antigens from the actual patient's tumor. This is achieved by inserting the EVIR into the dendritic cell, where it recognizes a protein on small vesicles called exosomes.

Exosomes are profusely released by the tumor and contain a variety of tumor antigens. They are also increasingly implicated in the promotion of metastasis and other processes that may facilitate the growth and spreading of cancer. By capturing exosomes coming from tumors, the EVIR helps the dendritic cells to precisely acquire tumor antigens from the cancer cells. The dendritic cells then present these antigens more efficiently to killer T cells, thus amplifying the patient's immune response against their tumor.

Imaging techniques also revealed that EVIRs promote the direct transfer of tumor antigens from the exosome surface to the outer membrane of the dendritic cell. This is a fascinating and unconventional route for antigen presentation to T cells,  which does not require complex and rate-limiting molecular interactions inside the dendritic cell.

The EVIR technology can intercept a natural phenomenon - the release of exosomes from tumors - to the patient's benefit, it exploits pro-tumoral exosomes as selective nanocarriers of tumor antigens, making them available to the immune system for cancer recognition and rejection. Although the new technology has the potential to increase the efficacy and specificity of dendritic cell vaccines, further pre-clinical work is required before it can be translated into a cancer treatment.
          haleplushearty.blogspot.com

How immune system's organ regenerates

A molecule called BMP4 that plays a key role in the thymus's extraordinary natural ability to recover from damage. Dr. Jarrod Dudakov of Fred Hutchinson Cancer Research Center, one of the study's leaders, talks about the importance of the thymus, the discoveries he and his colleagues have made about how it regenerates. The researchers hope to translate their work into new therapies to improve the function of the immune system in old age and make immunotherapies more effective.

The thymus is like a boot camp for new recruits to the immune system. From their birthplace in the bone marrow, immature white blood cells go to the thymus to mature into disease-killing machines. A healthy, active thymus gets you a diverse set of different T cells, each equipped to recognize and kill a slightly different foreign target. Thus, the organ is critical for a strong immune system that's ready to prevent any threat.

The thymus is sensitive to damage from everything from infections to life stress, it is also naturally resilient. Its power to bounce back from injury, however, fades with age, and it can take a serious hit from certain aggressive cancer therapies. BMP4, the molecule identified in the team's new study, is only the second known driver of natural thymic regeneration.

 The researchers found that BMP4 is produced by certain cells lining the inside of the organ. That molecule signals other cells of the thymus to turn on genes that promote development and repair.
Now, the team is working to figure out whether there's a master trigger that activates the whole regeneration process and then translate that knowledge into new therapies that help patients.
          haleplushearty.blogspot.com

Activation of immune T cells changes behavior

Researchers have discovered that T cells immune cells that protect the body from infections and cancer change the body's metabolism when they are activated, and that this activation leads to changes in behavior.

It is currently known that individual T cells change their metabolism to meet their energy needs after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored.

 To understand the systemic effects, the group looked at T cell activation in mice designed to lack a surface receptor called PD-1, which is necessary for inhibiting the activity of T cells. T cells remain activated in mice without the receptor, similar to those in the immune systems of people with certain types of autoimmune disease.

In these mice, they found that amino acids molecules that are used to build proteins were depleted in the blood, and that they were increased in the T cells themselves, implicating the T cells in the change. The team tracked and imaged amino acids in many organs, and found that the depletion of amino acids from the blood was taking place due to the accumulation of amino acids in activated T cells in the lymph nodes, showing that strong or long lasting immune responses can cause metabolic changes elsewhere in the body.

Researchers analyzed the biochemistry of the brain, they found that the systemic decrease in the amino acids tryptophan and tyrosine in blood led to lower amounts available in the brain, limiting production of the neurotransmitters serotonin and dopamine. These neurotransmitters affect emotions, motivation and fear.

Serotonin is often a target of drugs that combat depression. The researchers found that their depletion in mice without PD-1 resulted in behavioral changes dominated by anxiety and exacerbated fear responses, which could be remedied by providing a diet rich in an essential amino acid.
          haleplushearty.blogspot.com

How to rearrange immune system cells

Immune system imbalanced due to overly-active cells or cells that suppress its function can cause different diseases. Manipulating the function of  T cells, could restore the immune system's balance and create new treatments for any diseases.

Pro-inflammatory cells that boost the immune system can be rearrange into anti-inflammatory cells that suppress disease. Effector T cells activate the immune system to defend human body against different pathogens while regulatory T cells control the immune system and prevent it from attacking healthy parts of its cells.

This rearrangement can be used in the treatment of autoimmune diseases and immuno-oncology therapies. The use of molecule drug that can rearrange effector T cells into regulatory T cells is very important for strengthening  immune systems. This metabolic mechanism changes one cell type into another.

In autoimmune disease, effector T cells are activated and cause damage to the body. Changing these cells into regulatory T cells could reduce the hyperactivity and return balance to the immune system. This rearrangement could improve therapies using stem cells, promotes immune tolerance and prevents the body from rejecting newly-transplanted cells.

Some cancers control regulatory T cells to suppress the immune system and allowing tumors to grow without detection. This process can activate the immune system, recognize cancer cells and attack them.
          haleplushearty.blogspot.com

Gene editing kills HIV-1 infection in animals

A permanent cure for HIV infection remains difficult because the virus can hide in their reservoirs.

 Scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) and the University of Pittsburgh show that they can remove HIV DNA from the genomes of living animals to prevent further infection.

They  demonstrate that HIV-1 replication can be removed completely and the virus eliminated from infected cells in animals with a powerful gene editing technology known as CRISPR/Cas9.

Previously, scientists used transgenic rat and mouse models with HIV-1 DNA incorporated into the genome of every tissue of the animals' bodies. They demonstrated that their strategy could delete the targeted fragments of HIV-1 from the genome in most tissues in the experimental animals.

In the new study, the team genetically inactivated HIV-1 in transgenic mice, reducing the RNA expression of viral genes by roughly 60 to 95 percent, confirming their earlier findings. They then tested their system in mice acutely infected with EcoHIV, the mouse equivalent of human HIV-1.

"During acute infection, HIV actively replicates. With EcoHIV mice, scientists were able to investigate the ability of the CRISPR/Cas9 strategy to block viral replication and potentially prevent systemic infection." The excision efficiency of their strategy reached 96 percent in EcoHIV mice, providing the first evidence for HIV-1 eradication by prophylactic treatment with a CRISPR/Cas9 system.

In the third animal model, latent HIV-1 infection was recapitulated in humanized mice engrafted with human immune cells, including T cells, followed by HIV-1 infection.

 "These animals carry latent HIV in the genomes of human T cells, where the virus can escape detection," Dr. Hu explained. Following a single treatment with CRISPR/Cas9, viral fragments were successfully excised from latently infected human cells embedded in mouse tissues and organs.

In all three animal models, the researchers utilized a recombinant adeno-associated viral (rAAV) vector delivery system based on a subtype known as AAV-DJ/8. "The AAV-DJ/8 subtype combines multiple serotypes, giving us a broader range of cell targets for the delivery of our CRISPR/Cas9 system,"

New HIV reservoir discovered by scientists

Scientists have discovered a new cell in human body where HIV persists in spite of treatment.

Researchers have tried to clear HIV virus from the white blood cells that is part of immune system.

The virus persists in macrophages of infected person, this shows that T cells and some other cells in the body can serve as reservoir for HIV.

Macrophages are large white blood cell in tissue and bloodstream, the discovery shows that macrophages can be infected and they respond to antiretroviral therapy.

Scientists discovered that macrophages can survive in the body and continue to attack the HIV positive patients when their is therapy interruption.

Victor Garcia, a professor of medicine, microbiology and immunology and his team are trying to find out how HIV continues in tissue macrophages during HIV treatment and how it respond to treatment.