Children's immune response more effective against COVID-19 -- ScienceDaily

New findings and novel technology could inform COVID-19 treatment and vaccine-development efforts — ScienceDaily

  • April 8, 2021

Two studies published in the open-access journal PLOS Pathogens provide new evidence supporting an important role for the immune system in shaping the evolution of SARS-CoV-2, the virus that causes COVID-19. These findings — and the novel technology behind them — improve understanding of how new SARS-CoV-2 strains arise, which could help guide treatment and vaccination efforts.

For the first study, Rachel Eguia of Fred Hutchinson Cancer Research Center in Seattle, Washington, and colleagues sought to better understand SARS-CoV-2 by investigating a closely related virus that has circulated widely for a far longer period of time: the common-cold virus 229E.

229E and SARS-CoV-2 are both in the coronavirus family, which features a “spike protein” that enables infection of human cells. A person who is infected with 229E develops an immune response against the spike protein that protects them from reinfection, but only for a few years. Whether reinfection then occurs because the immune response wears off or because 229E evolves to escape it has been unclear.

Eguia and colleagues addressed this question by testing the activity of serum samples collected from patients in the 1980s-90s against spike proteins from both old 229E strains and strains that evolved later on. They found that the old spike proteins were vulnerable to the older sera. However, modern spike proteins were able to evade older sera while remaining vulnerable to sera from modern patients.

This analysis suggests that modern strains of 229E have accumulated spike protein mutations that enable them to evade older sera. These findings raise the possibility that SARS-CoV-2 and other coronaviruses could undergo similar evolution, and that COVID-19 vaccines may require periodic updates to remain effective against new strains.

The authors add, “The human common-cold coronavirus evolves over the span of years to decades to erode neutralization by human polyclonal serum antibodies. This work suggests that human coronaviruses undergo significant antigenic evolution that may contribute to eventual re-infections.”

For the second study, Sung Hee Ko of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and colleagues developed new technology for genetic sequencing of the SARS-CoV-2 spike protein, enabling detection of multiple SARS-CoV-2 strains that may be present at the same time within a single infected patient.

Previous studies have used standard sequencing methods to produce a single genetic sequence from an individual patient, obscuring the potential presence of multiple SARS-CoV-2 strains. By contrast, the new technology highlights virus diversity within each patient and enables tracking of the evolution of new SARS-CoV-2 strains during acute infection.

Indeed, when the researchers applied the new method to human respiratory samples, they found new SARS-CoV-2 variants arising within the same patient over the course of acute infection. The precise mutations in these variants suggest that they arose in response to selective pressure from the immune system.

Future application of the new technology could improve understanding of how the evolution of new SARS-CoV-2 variants within a single patient impacts their outcomes. The findings also suggest that patients might see greater benefits from early treatment with antiviral drugs capable of targeting multiple strains, than from delayed treatment with a single antiviral drug.

The authors add, “We used new technology to show that coronavirus variants with mutated spike proteins can arise early in the course of infection. Our results suggest more virus evolution in each person than previously thought, with potential implications for clinical outcomes and for the emergence of transmissible variant strains.”

Together, these two studies deepen understanding of how new SARS-CoV-2 strains arise in response to immune system activity, potentially paving the way for additional research and improved treatment.

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Inflammation-fighting protein could improve treatment of rheumatoid arthritis

Inflammation-fighting protein could improve treatment of rheumatoid arthritis

  • March 29, 2021

IMAGE

IMAGE: Study authors Mahamudul Haque, Salah-Uddin Ahmed, and Anil K. Singh look at a protein array in their lab at the WSU Health Sciences Spokane campus.
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Credit: Photo by Cori Kogan, Washington State University Health Sciences Spokane

SPOKANE, Wash. – New research led by scientists at Washington State University has found that a protein known as GBP5 appears to play a key role in suppressing inflammation in rheumatoid arthritis, a potentially debilitating disease in which the immune system mistakenly attacks the body’s own joint tissues.

Published in the journal Arthritis & Rheumatology, the discovery could someday lead to new treatments to slow or halt the progress of the disease, which affects an estimated 1.5 million Americans. The researchers said it may also have applications in other inflammatory diseases.

First author Mahamudul Haque first stumbled upon GBP5 back in 2015, when he was working toward a Ph.D. in pharmaceutical sciences in WSU’s College of Pharmacy and Pharmaceutical Sciences. Now a postdoctoral research associate in the WSU Elson S. Floyd College of Medicine, Haque had been tasked with comparing the expression of different genes in joint tissue from rheumatoid arthritis patients and non-diseased joint tissue. Among the thousands of genes included in his analysis, one gene stood out in particular because its expression level was several times greater in rheumatoid arthritis tissue. That gene was guanylate binding protein 5 (GBP5), which helps produce the GBP5 protein.

“That caught our attention and interest,” said senior author Salah-Uddin Ahmed, a professor in the College of Pharmacy and Pharmaceutical Sciences who oversaw the work.

As far as Ahmed and Haque could tell, no other studies had looked at the role of GBP5 in rheumatoid arthritis or other auto-immune diseases, so they decided to take on the task.

The inflammation seen in rheumatoid arthritis causes painful swelling of joint tissues that can result in bone loss and deformed joints. Previous research conducted by Ahmed and his team has suggested that this inflammation is driven primarily by a cytokine protein known as interleukin-1 beta (IL-1 beta). To find out what role GBP5 plays, the researchers designed a series of experiments using rheumatoid arthritis synovial fibroblasts, a type of cell located in the tissue that lines joints and is known to play a role in inflammation and joint destruction. When they manipulated the cells to stop producing GBP5 and then added IL-1 beta to induce inflammation, they saw much higher levels of inflammation in cells that lacked GBP5 versus in non-manipulated cells. What’s more, when they increased levels of GBP5 in those same cells, inflammation triggered by IL-1 beta went down.

“Our initial thought had been that the GBP5 protein played a role in causing the disease, but as we worked to decipher the mechanism of GBP5 in rheumatoid arthritis we found that it was induced in response to inflammation and was trying to cut back inflammation before it goes out of control,” Ahmed said.

In addition, their research revealed how GBP5 interacts with interferon gamma, another cytokine that has been shown to fight inflammation under certain circumstances. When they silenced the GBP5 gene, the researchers found that it reduced interferon gamma’s ability to fight the inflammation triggered by IL-1 beta. This suggests that, on top of having its own anti-inflammatory effect, GBP5 also supports the anti-inflammatory function of interferon gamma.

Finally, the researchers confirmed their findings in a rodent model of rheumatoid arthritis, which showed that joint inflammation and bone loss increased when the GBP5 gene was turned off.

Ahmed said he and his team are conducting additional research to confirm that their findings hold up in other pre-clinical models of rheumatoid arthritis. Pending further, clinical studies to test this concept in rheumatoid arthritis patients at different stages of the disease, Ahmed said their findings could someday lead to the development of new combination therapies that could boost GBP5 levels to reduce inflammation and bone loss.

“What we would like to understand is, if we introduced this protein very early during the onset of rheumatoid arthritis, could we reverse or suppress the course of the disease?” Ahmed said.

Haque also suggested that researchers should take a closer look at the role of GBP5 in other conditions that involve inflammation. This includes other types of arthritis, such as gout and osteoarthritis.

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In addition to Haque and Ahmed, authors on the paper include Anil K. Singh–an assistant research professor in the Ahmed lab at WSU –and Madhu Ouseph, a pathologist who was at the Stanford University School of Medicine and is now at Weill Cornell Medical College.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01AR072615 and from internal funds provided by Washington State University. Support for the initial findings that laid the groundwork for this study came from the Rheumatology Research Foundation.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

UC San Diego launches first-of-its-kind clinical trial to see if mushrooms can fight COVID

UC San Diego launches first-of-its-kind clinical trial to see if mushrooms can fight COVID

  • March 25, 2021

SAN DIEGO, Calif. — Scientists continue to search for better treatments for COVID-19, and researchers at UC San Diego think one solution might be growing on trees.

They’ve just launched a clinical trial to see if certain mushrooms can help treat the disease in its early stages. The trial, which is enrolling volunteers now, is the first study of its kind authorized by the Food and Drug Administration.

“We think mushrooms may have the ability to reduce the severity of COVID,” said principal investigator Dr. Gordon Saxe. Saxe is a preventive and integrative medicine physician who leads the Krupp Center for Integrative Research at UCSD.

Mushrooms have been used in medicine for thousands of years, notably by the Greeks and Chinese. Studies have shown the fungi have a range of pathogen-fighting and immune-boosting properties.

The first antibiotic, penicillin, was derived from a mushroom.

These medicinal properties are a byproduct of evolution, Saxe said. Mushrooms and other fungi can be infected by viruses and bacteria just like humans, so they developed defenses over time.

“They evolved all kinds of amazing antimicrobial defenses against viruses in particular, and we can benefit from what they have produced. The medicines they contain can get conveyed to us when we ingest them,” he said.

There are about 12,000 known species of mushrooms and Dr. Saxe’s team has honed in on two: turkey tail and agarikon. Both are native to old growth forests in North America. They do not have hallucinogenic properties.

“They are no more psychoactive than the button mushrooms you would put in a stir fry,” Saxe said.

In lab tests, agarikon has shown strong antiviral activity against drug-resistant strains of tuberculosis along with H1N1 (swine flu), H5N1 (bird flu), cowpox and herpes viruses, according to mushroom expert Paul Stamets, a collaborator on the study.

In some experiments, compounds in agarikon were 10 times more potent against flu viruses than the pharmaceutical ribavirin, Stamets said.

Dr. Saxe is now recruiting 132 volunteers recently diagnosed with COVID-19 for the double-blind, controlled study at UCSD and UCLA. Volunteers will take capsules of mushroom powder or a placebo three times a day for up to two weeks. Participants will be compensated $250.

Interested volunteers should email covid19trial@ucsd.edu or call (858) 249-6896.

Other studies are already in the works. Research has shown mushrooms can boost the immune system, particularly helper T cells that orchestrate antibodies. Dr. Saxe is planning to launch a second FDA authorized study as early as May to explore whether taking mushrooms can stimulate a stronger response to the COVID-19 vaccines.

A third COVID study will explore a Chinese herbal formula that has been used in Eastern Medicine for more than two millennia.

“People are realizing that there was wisdom in some of the ancient approaches, but we need to retest these things using modern science,” Dr. Saxe said.

This story was first published by Derek Staahl at KGTV.

Can mushrooms fight COVID? UC San Diego launches first-of-its-kind clinical trial

Can mushrooms fight COVID? UC San Diego launches first-of-its-kind clinical trial

  • March 24, 2021

SAN DIEGO (KGTV) — Scientists continue to search for better treatments for COVID-19, and researchers at UC San Diego think one solution might be growing on trees.

They’ve just launched a clinical trial to see if certain mushrooms can help treat the disease in its early stages. The trial, which is enrolling volunteers now, is the first study of its kind authorized by the Food and Drug Administration.

“We think mushrooms may have the ability to reduce the severity of COVID,” said principal investigator Dr. Gordon Saxe. Saxe is a preventive and integrative medicine physician who leads the Krupp Center for Integrative Research at UCSD.

Mushrooms have been used in medicine for thousands of years, notably by the Greeks and Chinese. Studies have shown the fungi have a range of pathogen-fighting and immune-boosting properties.

The first antibiotic, penicillin, was derived from a mushroom.

These medicinal properties are a byproduct of evolution, Saxe said. Mushrooms and other fungi can be infected by viruses and bacteria just like humans, so they developed defenses over time.

“They evolved all kinds of amazing antimicrobial defenses against viruses in particular, and we can benefit from what they have produced. The medicines they contain can get conveyed to us when we ingest them,” he said.

There are about 12,000 known species of mushrooms and Dr. Saxe’s team has honed in on two: turkey tail and agarikon. Both are native to old growth forests in North America. They do not have hallucinogenic properties.

“They are no more psychoactive than the button mushrooms you would put in a stir fry,” Saxe said.

In lab tests, agarikon has shown strong antiviral activity against drug-resistant strains of tuberculosis along with H1N1 (swine flu), H5N1 (bird flu), cowpox and herpes viruses, according to mushroom expert Paul Stamets, a collaborator on the study.

In some experiments, compounds in agarikon were 10 times more potent against flu viruses than the pharmaceutical ribavirin, Stamets said.

Dr. Saxe is now recruiting 132 volunteers recently diagnosed with COVID-19 for the double-blind, controlled study at UCSD and UCLA. Volunteers will take capsules of mushroom powder or a placebo three times a day for up to two weeks. Participants will be compensated $250.

Interested volunteers should email covid19trial@ucsd.edu or call (858) 249-6896.

Other studies are already in the works. Research has shown mushrooms can boost the immune system, particularly helper T cells that orchestrate antibodies. Dr. Saxe is planning to launch a second FDA authorized study as early as May to explore whether taking mushrooms can stimulate a stronger response to the COVID-19 vaccines.

A third COVID study will explore a Chinese herbal formula that has been used in Eastern Medicine for more than two millennia.

“People are realizing that there was wisdom in some of the ancient approaches, but we need to retest these things using modern science,” Dr. Saxe said.

New therapy extends breast cancer survival rate, prevents reoccurrence

Common inflammatory bowel disease treatment linked to reduced COVID-19 antibody response

  • March 22, 2021

New evidence indicates the commonly-prescribed inflammatory bowel disease (IBD) drug infliximab blunts the immune system to COVID-19 infection, potentially increasing the risk of reinfection.

The findings arose from the CLARITY study, which recruited 6,935 patients with Crohn’s disease and ulcerative colitis from 92 UK hospitals between September and December 2020. It found that fewer than half of people with IBD who were treated with infliximab had detectable antibodies after SARS-CoV-2 infection, the coronavirus that causes COVID-19.

The study is led by gastroenterologists at the Royal Devon and Exeter NHS Foundation Trust and the University of Exeter Medical School and supported by Crohn’s and Colitis UK and the UK National Institute for Health Research (NIHR).

The authors say an impaired immune response may boost susceptibility to recurrent COVID-19 and help drive the evolution of new variants of SARS-CoV-2, the virus responsible for the infection, warn the researchers. However, they are encouraging people to continue to take their medication as overall Covid-19 risk remains very low.

Careful monitoring of patients with IBD treated with infliximab, who have been vaccinated against COVD-19, will be needed to ensure they mount a strong enough antibody response to ward off the infection, they advise.
CLARITY study lead, Professor Tariq Ahmad, of the University of Exeter Medical School, said: “The poor antibody responses observed in patients treated with infliximab raise the possibility that some patients may not develop protective immunity after COVID-19 infection, and might be at increased risk of reinfection. What we don’t yet know is how use of anti-TNF drugs will impact antibody responses to vaccination.”

The study underlines the importance of fast-paced research to address important questions in people affected by IBD. Professor Ahmad said: “The CLARITY IBD study will continue to follow participants for 40 weeks to investigate important questions regarding the impact of immunosuppressive drugs on immunity to SARS-CoV-2 infection and COVID-19. Modified vaccine schedules may be required if impaired antibody responses are also observed following vaccination. However, because the overall risk of COVID-19 is low in this patient group, we would still strongly encourage patients to continue to take anti-TNF medicines.”

Around two million people worldwide are prescribed anti-tumour necrosis factor (anti-TNF)drugs, which include infliximab. Anti-TNF drugs are effective treatments for immune-mediated inflammatory diseases, but by suppressing the immune system, they can reduce vaccine effectiveness and increase risk of serious infection. The CLARITY study, published in GUT, sought to investigate the impact of infliximab on immune responses to SARS-CoV-2 in patients with IBD.

500,000 people across the UK live with Inflammatory bowel disease (IBD) of which ulcerative colitis and Crohn’s disease, are the two main forms. Symptoms include urgent and frequent bloody diarrhoea, weight loss, pain, and extreme fatigue. At the start of the COVID-19 pandemic the UK Government advised that patients taking anti-TNF medicines could be at increased risk of complications from coronavirus. All were advised to follow strict social distancing measures, and some, depending on the severity of their condition, were advised to shield.

In the CLARITY study researchers compared antibody responses to SARS-CoV-2 in patients treated with infliximab to an alternative medication, vedolizumab that blocks inflammatory cells entering the gut without reducing immune responses to infections or vaccinations.
Rates of COVID-19 infection and hospitalisations were similar between infliximab- and vedolizumab-treated patients. However, infliximab-treated patients were much less likely to subsequently have a positive antibody test. These findings could not, therefore, be explained by differences in acquisition or severity of infection alone. Rather, infliximab seemed to be directly influencing antibody responses to infection. In keeping with this idea, rates of positive antibody tests were lowest in participants who were also taking other drugs that suppress the immune system, such as azathioprine, mercaptopurine or methotrexate.

Dr Nick Powell, of Imperial College London, said the CLARITY team is now exploring the role of other elements of the immune system, which may still protect against reinfection. “Although we clearly observed diminished antibody responses in patients taking infliximab, we haven’t yet completed our investigation of T-cell and other protective immune responses against the virus. I would expect that even in the presence of less efficient antibody production, infliximab-treated patients will mobilise some protective aspect of their immune system to defend themselves.”

Professor Danny Altmann, Professor of Immunology, at Imperial College London, said: “Many people with IBD who are taking infliximab have been shielding throughout this pandemic, so little is known about their susceptibility to COVID-19. They’re not eligible for phase 3 trials so there’s also a knowledge gap around their vaccine response. At this stage it’s really key to start to collect the ‘real life’ data about their immunity and susceptibility. This study starts to offer some answers, including how best to understand and monitor how these individuals progress coming out of shielding and how well they respond to vaccination.”

Sarah Sleet, Chief Executive Officer at Crohn’s & Colitis UK, said: “The CLARITY results are an important first step in helping us understand how different medicines for Crohn’s and Colitis affect a person’s response to coronavirus. At this stage the key message is people with Crohn’s and Colitis should keep taking their medication to stay well and take the vaccine when offered. But we also need research like this to continue. A huge number of people with Crohn’s and Colitis have had to contend with the stresses of shielding and social distancing, and it’s vital this group is prioritised in research.”

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The paper is entitled “Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab”, published in GUT.

If you would like further information regarding this study please contact rde-tr.clarityibd@nhs.net or visit @CLARITYIBD for more updates.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

T-Cell Leukemia: Symptoms, Causes, Treatment, Outlook

T-Cell Leukemia: Symptoms, Causes, Treatment, Outlook

  • March 13, 2021

T-cell leukemia is an uncommon type of blood cell cancer that affects your white blood cells.

T cells are a type of white blood cell. The purpose of these blood cells is to help your body detect and fight off infection or illness.

These blood cells form and begin to develop in your bone marrow. Immature T cells leave your bone marrow and become mature T cells in your thymus gland, a small organ located behind your breast bone.

Damaged DNA in a T cell can cause uncontrolled cell growth and division. This overproduction of cells is how T-cell leukemia starts.

This article will help explain what T cell leukemia is, the typical symptoms, and how this condition is most often diagnosed and treated.

Leukemia is cancer of your blood cells and the tissues that make these blood cells.

There are many different kinds of leukemia. They’re classified according to whether they’re fast growing (acute) or slow growing (chronic) and by the type of blood cell involved. Most often leukemia involves white blood cells.

There are two kinds of white blood cells. Let’s look at each type in more detail.

Lymphoid cells

These white blood cells are known as lymphocytes, which are the main cells that make up lymph tissue, a major part of your immune system. They help your body fight infection. There are two main types of lymphocytes:

  • T cells. These cells circulate in your blood looking for infected or foreign cells. When they find one, they destroy the cell and send a signal that activates your immune system.
  • B cells. These cells produce antibodies to stop foreign invaders, like viruses or bacteria, from harming your body.
Healthline

Myeloid cells

When blood stem cells develop into new blood cells, they can either become lymphocytes or myeloid cells.

Myeloid cells can develop into white blood cells (other than lymphocytes), red blood cells, or platelets. The following types of white blood cells are all examples of mature myeloid cells:

Healthline

The four main types of leukemias that can develop include:

Blood cells are made in your bone marrow. Primitive stem cells form there and develop into immature precursor cells. Some of these stay in your bone marrow and become mature B cells. Other precursor cells leave your bone marrow and travel to your thymus where they become mature T cells.

Lymphocytic leukemia develops when the DNA in precursor cells change (mutate) or become damaged. Instead of maturing, the damaged DNA tells these cells to multiply uncontrollably. The result is a large number of abnormal copies of the cell in your bone marrow and bloodstream.

Lymphoma develops when this process occurs in a lymph node or other lymphatic tissue. Most lymphocytic leukemias involve B cells, but there are a few T-cell leukemias.

T-cell prolymphocytic leukemia (T-PLL) is a good example of cancer that affects your T cells, and it’s been studied more than other types.

In the rest of this article, we’ll focus on T-PLL when describing T-cell leukemia.

The most common symptom of T-PLL is an extremely high white blood cell count (lymphocytosis) of about 100,000 cells/microliter (mL) or more. The normal range is 4,000 to 11,000/mL.

Up to 30 percent of people with T-PLL have a high white blood cell count but no other symptoms. In this instance, T-PLL is stable or only progresses slowly. This is called inactive T-PLL.

Eventually, though, the disease becomes active and causes symptoms. This usually happens within 2 years of developing a high white blood cell count.

When symptoms are present, they might include:

  • a rash or other skin lesion caused by white blood cells moving into your skin tissue
  • fluid buildup in your abdominal cavity (ascites) or around your lungs (pleural effusion)
  • swelling and edema in your legs, the skin around your eyes, or the membrane covering your eye (conjunctiva)

Symptoms commonly associated with most other types of leukemia and lymphoma are uncommon in the early stages of T-PLL. But symptoms may appear as the illness progresses. So-called B-cell symptoms can develop, which include:

Sometimes, your bone marrow becomes overcrowded with the large number of T cells, so fewer red blood cells and platelets can be produced. This may cause:

There are also certain symptoms that may indicate white blood cells have infiltrated your organs. Your doctor may notice these during a physical exam and can include:

There aren’t many known risk factors for T-PLL. The average age of diagnosis is about 65, and men are diagnosed with the condition slightly more often than women. It hasn’t been found in children or young adults, except as described below.

You’re more likely to get T-PLL if you have ataxia telangiectasia. This is a rare inherited condition that begins in childhood and affects your immune and nervous systems.

The characteristic symptom is a progressive loss of the ability to coordinate movements (ataxia). As it worsens, activities like walking and balancing become more difficult.

People with ataxia telangiectasia are younger when they develop T-PLL. It usually begins at age 30 or younger.

Your doctor will first do a thorough physical exam. If they suspect some type of condition related to your blood, they’ll order your blood to be tested.

These tests will analyze your white blood cell count and also look for markers and other characteristics of your lymphocytes. Typical tests include:

  • a complete blood count with differential to determine the numbers of each kind of blood cell
  • a peripheral blood smear to evaluate the blood cells under a microscope
  • a flow cytometry to evaluate lymphocyte size, shape, surface markers, and other characteristics
  • an analysis of lymphocyte T-cell receptor arrangements
  • karyotyping to examine your chromosomes
  • fluorescence in situ hybridization (FISH) to look for genetic abnormalities

The information that’s gathered from these tests will help determine whether you meet the criteria for a diagnosis of T-PLL.

Additionally, testing for human T-lymphotropic virus (HTLV) type 1 is usually done. If it’s positive, it means you have adult T-cell leukemia/lymphoma, which is caused by the virus and not T-PLL.

A CT scan of your abdomen, pelvis, and chest will usually be done prior to treatment to evaluate your major organs, such as your liver, spleen, and lymph nodes.

Red blood cells or platelets are usually also evaluated with a bone marrow biopsy before treatment begins.

If you’re asymptomatic, you’ll be followed closely with monthly physical exams and white blood cell counts until your T-PLL becomes active.

Since there’s no benefit until it becomes active, asymptomatic, inactive T-PLL isn’t treated.

Active T-PLL is treated with chemotherapy. The drug of choice is alemtuzumab (Lemtrada), either alone or in combination with other drugs.

The response rate to this drug is as high as 90 percent, with up to 80 percent of people achieving complete remission. Although the response to first time chemotherapy can be good, relapse usually occurs within 2 years of remission.

For anyone in complete remission, an allogenic stem cell transplant — which can involve donations from bone marrow or blood — will be considered. However, finding a suitable donor can be difficult.

If there’s no donor available, an autologous stem cell transplant — which is a sample collected from you before chemotherapy — may be a good option.

T-PLL is a very aggressive type of leukemia. On average, people with T-PLL live about 20 months after diagnosis. This hasn’t changed significantly in over 30 years, even as newer and better treatments have become available.

When relapse occurs, remission can be achieved again using a “plan b” medication or treatment option, but it typically lasts only 6 to 9 months.

Although it’s a rare disease, T-PLL is one of the most common T-cell leukemias. It’s very aggressive and requires treatment early on. The most common symptom of this T-cell leukemia is a very high white blood cell count.

The diagnosis is made by physical exam and various types of blood tests to determine T-cell characteristics.

When you’re symptomatic, early treatment with intravenous chemotherapy is recommended. Stem cell transplant is considered for anyone who achieves complete remission.

watercolor illustration of coronavirus cells

Coronavirus Deranges the Immune System in Complex and Deadly Ways

  • March 4, 2021


This story also ran on USA Today. It can be republished for free.

There’s a reason soldiers go through basic training before heading into combat: Without careful instruction, green recruits armed with powerful weapons could be as dangerous to one another as to the enemy.

The immune system works much the same way. Immune cells, which protect the body from infections, need to be “educated” to recognize bad guys — and to hold their fire around civilians.

In some covid patients, this education may be cut short. Scientists say unprepared immune cells appear to be responding to the coronavirus with a devastating release of chemicals, inflicting damage that may endure long after the threat has been eliminated.

“If you have a brand-new virus and the virus is winning, the immune system may go into an ‘all hands on deck’ response,” said Dr. Nina Luning Prak, co-author of a January study on covid and the immune system. “Things that are normally kept in close check are relaxed. The body may say, ‘Who cares? Give me all you’ve got.’”

While all viruses find ways to evade the body’s defenses, a growing field of research suggests that the coronavirus unhinges the immune system more profoundly than previously realized.

Some covid survivors have developed serious autoimmune diseases, which occur when an overactive immune system attacks the patient, rather than the virus. Doctors in Italy first noticed a pattern in March 2020, when several covid patients developed Guillain-Barré syndrome, in which the immune systems attacks nerves throughout the body, causing muscle weakness or paralysis. As the pandemic has surged around the world, doctors have diagnosed patients with rare, immune-related bleeding disorders. Other patients have developed the opposite problem, suffering blood clots that can lead to stroke.

All these conditions can be triggered by “autoantibodies” — rogue antibodies that target the patient’s own proteins and cells.

In a report published in October, researchers even labeled the coronavirus “the autoimmune virus.”

“Covid is deranging the immune system,” said John Wherry, director of the Penn Medicine Immune Health Institute and another co-author of the January study. “Some patients, from their very first visit, seem to have an immune system in hyperdrive.”

Although doctors are researching ways to overcome immune disorders in covid patients, new treatments will take time to develop. Scientists are still trying to understand why some immune cells become hyperactive — and why some refuse to stand down when the battle is over.

Key immune players called “helper T cells” typically help antibodies mature. If the body is invaded by a pathogen, however, these T cells can switch jobs to hunt down viruses, acting more like “killer T cells,” which destroy infected cells. When an infection is over, helper T cells usually go back to their old jobs.

In some people with severe covid, however, helper T cells don’t stand down when the infection is over, said James Heath, a professor and president of Seattle’s Institute for Systems Biology.

About 10% to 15% of hospitalized covid patients Heath studied had high levels of these cells even after clearing the infection. By comparison, Heath found lingering helper T cells in fewer than 5% of covid patients with less serious infections.

In affected patients, helper T cells were still looking for the enemy long after it had been eliminated. Heath is now studying whether these overzealous T cells might inflict damage that leads to chronic illness or symptoms of autoimmune disease.

“These T cells are still there months later and they’re aggressive,” Heath said. “They’re on the hunt.”

Friendly Fire

Covid appears to confuse multiple parts of the immune system.

In some patients, covid triggers autoantibodies that target the immune system itself, leaving patients without a key defense against the coronavirus.

In October, a study published in Science led by Rockefeller University’s Jean-Laurent Casanova showed that about 10% of covid patients become severely ill because they have antibodies against an immune system protein called interferon.

Disabling interferon is like knocking down a castle’s gate. Without these essential proteins, invading viruses can overwhelm the body and multiply wildly.

New research shows that the coronavirus may activate preexisting autoantibodies, as well as prompt the body to make new ones.

In the January study, half of the hospitalized covid patients had autoantibodies, compared with fewer than 15% of healthy people. While some of the autoantibodies were present before patients were infected with SARS-CoV-2, others developed over the course of the illness.

Other research has produced similar findings. In a study out in December, researchers found that hospitalized covid patients harbored a diverse array of autoantibodies.

While some patients studied had antibodies against virus-fighting interferons, others had antibodies that targeted the brain, thyroid, blood vessels, central nervous system, platelets, kidneys, heart and liver, said Dr. Aaron Ring, assistant professor of immunology at Yale School of Medicine and lead author of the December study, published online without peer review. Some patients had antibodies associated with lupus, a chronic autoimmune disorder that can cause pain and inflammation in any part of the body.

In his study, Ring and his colleagues found autoantibodies against proteins that help coordinate the immune system response. “These are the air traffic controllers,” Ring said. If these proteins are disrupted, “your immune system doesn’t work properly.”

Covid patients rife with autoantibodies tended to have the severest disease, said Ring, who said he was surprised at the level of autoantibodies in some patients. “They were comparable or even worse than lupus,” Ring said.

Although the studies are intriguing, they don’t prove that autoantibodies made people sicker, said Dr. Angela Rasmussen, a virologist affiliated with Georgetown’s Center for Global Health Science and Security. It’s possible that the autoantibodies are simply markers of serious disease.

“It’s not clear that this is linked to disease severity,” Rasmussen said.

The studies’ authors acknowledge they have many unanswered questions.

“We don’t yet know what these autoantibodies do and we don’t know if [patients] will go on to develop autoimmune disease,” said Dr. PJ Utz, a professor of immunology and rheumatology at Stanford University School of Medicine and a co-author of Luning Prak’s paper.

But recent discoveries about autoantibodies have excited the scientific community, who now wonder if rogue antibodies could explain patients’ differing responses to many other viruses. Scientists also want to know precisely how the coronavirus turns the body against itself — and how long autoantibodies remain in the blood.

‘An Unfortunate Legacy’

Scientists working round-the-clock are already beginning to unravel these mysteries.

A study published online in January, for example, found rogue antibodies in patients’ blood up to seven months after infection.

Ring said researchers would like to know if lingering autoantibodies contribute to the symptoms of “long covid,” which afflicts one-third of covid survivors up to nine months after infection, according to a new study in JAMA Network Open.

“Long haulers” suffer from a wide range of symptoms, including debilitating fatigue, shortness of breath, cough, chest pain and joint pain, according to the Centers for Disease Control and Prevention. Other patients experience depression, muscle pain, headaches, intermittent fevers, heart palpitations and problems with concentration and memory, known as brain fog.

Less commonly, some patients develop an inflammation of the heart muscle, abnormalities in their lung function, kidney issues, rashes, hair loss, smell and taste problems, sleep issues and anxiety.

The National Institutes of Health has announced a four-year initiative to better understand long covid, using $1.15 billion allocated by Congress.

Ring said he’d like to study patients over time to see if specific symptoms might be explained by lingering autoantibodies.

“We need to look at the same patients a half-year later and see which antibodies they do or don’t have,” he said. If autoantibodies are to blame for long covid, they could “represent an unfortunate legacy after the virus is gone.”

Widening the Investigation

Scientists say the coronavirus could undermine the immune system in several ways.

For example, it’s possible that immune cells become confused because some viral proteins resemble proteins found on human cells, Luning Prak said. It’s also possible that the coronavirus lurks in the body at very low levels even after patients recover from their initial infection.

“We’re still at the very beginning stages of this,” said Luning Prak, director of Penn Medicine’s Human Immunology Core Facility.

Dr. Shiv Pillai, a Harvard Medical School professor, notes that autoantibodies aren’t uncommon. Many healthy people walk around with dormant autoantibodies that never cause harm.

For reasons scientists don’t completely understand, viral infections appear able to tip the scales, triggering autoantibodies to attack, said Dr. Judith James, vice president of clinical affairs at the Oklahoma Medical Research Foundation and a co-author of Luning Prak’s study.

For example, the Epstein-Barr virus, best known for causing mononucleosis, has been linked to lupus and other autoimmune diseases. The bacteria that cause strep throat can lead to rheumatic fever, an inflammatory disease that can cause permanent heart damage. Doctors also know that influenza can trigger an autoimmune blood-clotting disorder, called thrombocytopenia.

Researchers are now investigating whether autoantibodies are involved in other illnesses — a possibility scientists rarely considered in the past.

Doctors have long wondered, for example, why a small number of people — mostly older adults — develop serious, even life-threatening reactions to the yellow fever vaccine. Three or four out of every 1 million people who receive this vaccine — made with a live, weakened virus — develop yellow fever because their immune systems don’t respond as expected, and the weakened virus multiplies and causes disease.

In a new paper in the Journal of Experimental Medicine, Rockefeller University’s Casanova has found that autoantibodies to interferon are once again to blame.

Casanova led a team that found three of the eight patients studied who experienced a dangerous vaccine reaction had autoantibodies that disabled interferon. Two other patients in the study had genes that disabled interferon.

“If you have these autoantibodies and you are vaccinated against yellow fever, you may end up in the ICU,” Casanova said.

Casanova’s lab is now investigating whether autoantibodies cause critical illness from influenza or herpes simplex virus, which can cause a rare brain inflammation called encephalitis.

Calming the Autoimmune Storm

Researchers are looking for ways to treat patients who have interferon deficiencies — a group at risk for severe covid complications.

In a small study published in February in the Lancet Respiratory Medicine, doctors tested an injectable type of interferon — called peginterferon-lambda — in patients with early covid infections.

People randomly assigned to receive an interferon injection were four times more likely to have cleared their infections within seven days than the placebo group. The treatment, which used a type of interferon not targeted by the autoantibodies Casanova discovered, had the most dramatic benefits in patients with the highest viral loads.

Lowering the amount of virus in a patient may help them avoid becoming seriously ill, said Dr. Jordan Feld, lead author of the 60-person study and research director at the Toronto Centre for Liver Disease in Canada. In his study, four of the placebo patients went to the emergency room because of breathing issues, compared with only one who received interferon.

“If we can bring the viral levels down quickly, they might be less infectious,” Feld said.

Feld, a liver specialist, notes that doctors have long studied this type of interferon to treat other viral infections, such as hepatitis. This type of interferon causes fewer side effects than other varieties. In the trial, those treated with interferon had similar side effects to those who received a placebo.

Doctors could potentially treat patients with a single injection with a small needle — like those used to administer insulin — in outpatient clinics, Feld said. That would make treatment much easier to administer than other therapies for covid, which require patients to receive lengthy infusions in specialized settings.

Many questions remain. Dr. Nathan Peiffer-Smadja, a researcher at the Imperial College London, said it’s unclear whether this type of interferon does improve symptoms.

Similar studies have failed to show any benefit to treating patients with interferon, and Feld acknowledged that his results need to be confirmed in a larger study. Ideally, Feld said, he would like to test interferon in older patients to see whether it can reduce hospitalizations.

“We’d like to look at long haulers, to see if clearing the virus quickly could lead to less immune dysregulation,” Feld said. “People have said to me, ‘Do we really need new treatments now that vaccines are rolling out?’ Unfortunately, we do.”

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

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Genetics Play a Role in Our Immune Response to Cancer Treatment

Genetics Play a Role in Our Immune Response to Cancer Treatment

  • February 11, 2021

Checkpoint inhibitors have been a breakthrough treatment for cancer, however, they only benefit about 15% of patients across different types of cancer. Thus, there is an unmet need to accurately predict which cancer patients will respond to checkpoint inhibitors.

A new study has found that inherited genetic variation plays a role in who is likely to benefit from checkpoint inhibitors, which release the immune system’s brakes so it can attack cancer. The study also points to potential new targets that could help even more patients unleash their immune system’s natural power to fight off malignant cells.

Their findings are published in the journal Immunity in a paper titled, “Germline genetic contribution to the immune landscape of cancer.”

“Understanding the contribution of the host’s genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA,” the researchers wrote.

“There are some factors that are already associated with how well the immune system responds to tumors,” explained Elad Ziv, MD, professor of medicine at the University of California, San Francisco (UCSF), and co-senior author of the paper, “But what’s been less studied is how well your genetic background predicts your immune system’s response to the cancer. That’s what is being filled in by this work: How much is the immune response to cancer affected by your inherited genetic variation?”

The researchers’ findings suggest that for a range of important immune functions, as much as 20% of the variation in how different people’s immune systems are able to attack cancer is due to the kind of genes they were born with, which are known as germline genetic variations.

“Rather than testing selected genes, we analyzed all the genetic variants we could detect across the entire genome. Among all of them, the ones with the greatest effect on the immune system’s response to the tumor were related to interferon signaling. Some of these variants are known to affect our response to viruses and our risk of autoimmune disorders,” added Davide Bedognetti, MD, PhD, director of the cancer program at the Sidra Medicine Research Branch in Doha, Qatar, and co-senior author of the paper. “As observed with other diseases, we demonstrated that specific genes can also predispose someone to have a more effective anticancer immunity.”

The researchers identified variants in 22 regions in the genome, or in individual genes, with significant effects.

The IFIH1 variants act on cancer immunity in different ways. For instance, people with the variant that confers risk of type 1 diabetes had a more inflamed tumor, which suggests they would respond better to cancer immunotherapy. The researchers, however, saw the opposite effect for patients with the variant associated with Crohn’s, indicating they might not benefit.

Another gene, STING1, was already thought to play a role in how patients respond to immunotherapy, and drug companies are looking for ways to boost its effects. But the researchers discovered that some people carry a variant that makes them less likely to respond, which may require further stratification of patients to know who could benefit most from those efforts.

But the 22 regions or genes identified in the new study are just the tip of the iceberg, the researchers said, and they suspect many more germline genes are likely to play a role in how the immune system responds to cancer.

The next step is to use the data to formulate “polygenic” approaches—taking a large number of genes into account to predict which cancer patients will benefit from current therapies, and developing new drugs for those who will not.

“It’s further off,” he said, “but it’s a big part of what we hope will come out of this work.”

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Fecal Transplants Are Showing Promise as a New Treatment For a Type of Skin Cancer

  • February 8, 2021

The effect of a drug, or impact of a treatment like chemotherapy, doesn’t just depend on your body. The success of a particular medicine also depends on the trillions of bacteria in your gut.

 

The 100 trillion bacteria that live within the human digestive tract – known as the human gut microbiome – help us extract nutrients from food, boost the immune response and modulate the effects of drugs.

Recent research, including my own, has implicated the gut microbiome in seemingly unconnected states, ranging from the response to cancer treatments to obesity and a host of neurological diseases, including Alzheimer’s, Parkinson’s disease, depression, schizophrenia and autism.

What underlies these apparently discrete observations is the unifying idea that the gut microbiota send signals beyond the gut and that these signals have broad effects on a large swathe of target tissues.

I am a medical oncologist whose research involves developing novel therapies for melanoma. To evaluate whether altering the microbiome could benefit cancer patients, my colleagues and I evaluated the transfer of fecal matter from melanoma patients who responded well to immunotherapy to those patients for whom immunotherapy failed.

Just published in the journal Science, our results reveal that this treatment helped shrink the tumors of advanced melanoma patients when other therapies hadn’t worked.

 

What connects cancer and gut bacteria?

Gut microbiota have been linked to to the success and failure of multiple cancer treatments, including chemotherapy and cancer immunotherapy with immune checkpoint inhibitors such as nivolumab and pembrolizumab.

In the more recent studies, the species and relative populations of gut bacteria determined the probability that a cancer patient would respond to drugs known as “immune checkpoint inhibitors.”

This research showed that differences in the gut microbiome between individual patients were associated with various outcomes to these drugs. But the precise mechanisms underlying microbiome-immune interactions remain unclear.

Can fecal microbes help drugs reach hard to treat melanoma?

Oncologists often treat patients with advanced melanoma using immunotherapies targeting specific proteins on the surface of immune cells known as PD-1 and CTLA-4. These work in a subset of patients, however – 50-70 percent of patients have cancers that get worse despite treatment.

No medical treatments have been approved to treat melanoma patients who have failed PD-1 immunotherapies.

To investigate whether certain types of microbes could boost the efficacy of PD-1 immunotherapies, my colleagues and I developed a study in which we collected fecal microbes from patients who had responded well to this therapy and administered these to cancer patients who didn’t benefit from the checkpoint drugs.

We chose stool from patients who responded well to immunotherapy based on the hunch that they would have greater quantities of bacteria implicated in helping shrink the cancer.

file 20210204 24 1wpdow3(Diwakar Davar/CC BY-ND)

As it is difficult to identify one or two species of bacteria that are responsible for the beneficial response to these therapies, we used the entire bacterial community – hence fecal microbe transplant.

Transplant recipients were patients whose melanoma had never responded to immunotherapy. Both recipients and donors underwent screening for diseases to ensure that no infectious agents would be transmitted during the transplant.

 

Following a biopsy of their tumor, patients received a fecal microbe transplant from patients who benefited from immunotherapy along with a drug called called pembrolizumab, which was continued every three weeks.

My colleagues and I assessed the fecal microbe transplant 12 weeks after the treatment. Patients whose cancers had shrunk or remained the same size after the fecal microbe transplant continued to receive pembrolizumab for up to two years.

Results of novel clinical trial

file 20210204 20 lkqki8(Diwakar Davar/CC BY-ND)

Following this fecal microbe transplant treatment, tumors of six out of 15 patients in the study had tumors that shrank or remained the same. The treatment was well tolerated, though some of the patients experienced minor side effects including fatigue.

When we analyzed the gut microbiota of treated patients, we observed that the six patients whose cancers had stabilized or improved showed increased numbers of bacteria that had previously been associated with responses to immunotherapy.

My colleagues and I also analyzed the blood and tumors from responders. In doing so, we observed that the responders had lower levels of adverse immune cells termed myeloid cells, and higher levels of memory immune cells. Additionally, by analyzing proteins in the blood serum of treated patients, we observed reductions in levels of key immune system molecules associated with resistance in responders.

These results suggest that introducing certain intestinal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells.

Ultimately we hope to move beyond fecal microbe transplants to specific collections of microbes in cancers besides melanoma, paving the way for standardized microbe-based drug therapy to treat immunotherapy-resistant tumors. The Conversation

Diwakar Davar, Assistant Professor of Medicine, University of Pittsburgh.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

 

How Biomarkers Impact Treatment Decisions in Lung Cancer

How Biomarkers Impact Treatment Decisions in Lung Cancer

  • January 28, 2021

Treatments for lung cancer have recently become more personalized thanks to the increasing study and use of biomarker testing in patients prior to immunotherapy treatment. Biomarkers provide clinicians with insight as to what treatments may work best, and the widespread use of biomarker testing is helping to drive treatment decisions and improve outcomes.

At the CURE® Educated Patient® Lung Cancer Summit, Dr. Melissa Johnson discussed the different types of biomarkers that are driving decisions for patients with small cell lung cancer (SCLC). Her main focus was on the widespread PD-L1 tumor mutation burden and microsatellite instability (MSI) that are known for their roles in other cancers but play an important role in determining immunotherapy treatment for patients with SCLC.

In an interview with CURE®, Dr. Johnson, director of the lung cancer program at the Sarah Cannon Caner Center in Nashville, Tennessee, discussed how these biomarkers help drive treatment decisions.

CURE®: Can you explain what a biomarker is and what you look for when you take a biopsy?

Johnson: The way I explain this to my patients is those immunotherapy biomarkers are indications on the tumor tissue, that the immune system knows that the cancer is present. If we take a step back, your immune system should recognize the cancer because it’s foreign to your body just like your immune system recognizes viruses, bacteria, or other foreign invaders. So when a cancer is able to grow, there’s something that is evading the normal immune system surveillance.

The way these immune therapy drugs work, they boost a patient’s own immune system but what we know is that if the immune system doesn’t recognize the cancer, (and) if the immune system is ignoring the cancer, then these therapies won’t work. So, the biomarkers indicate that a patient’s immune system knows that the tumor is there; that there’s just something impeding the immune system’s ability to attack. And those are patients in whom immune therapies are likely to bring benefit to, when the immune system is able to recognize it and go after it.

How are markers like PD-L1 and MSI linked?

They are related. Microsatellite instability, you can think of as a super, super high tumor mutation burden. Tumor mutation burden is scoring a likelihood based on a particular tumor, that they’ll be neo-antigens in the tumor that the immune system can recognize. And this is a calculated score that is done on next generation sequencing profiles. So, if your cancer has been profiled using Foundation One, Kerris, even Tempus, all of those vendors have the ability to calculate a tumor mutation burden score.

Then, Keytruda (pembrolizumab) is approved for patients whose tumor mutation burden is higher than 10, so that’s one way that this biomarker is being used. Lung cancer is not a tumor where we check microsatellite instability, routinely, that’s more often used in colorectal cancer, and has been associated with response to chemo therapies that are used for colorectal cancer. So, I would say that if you are a lung cancer patient, you should ask your oncologist about the PD-L1 biomarker and the TMB (tumor mutation burden) biomarker. The MSI microsatellite instability has also been done on your tumor if you’ve had next generation sequencing, but we don’t talk about it quite as much in lung cancer.

What kind of immunotherapy is being given based off these biomarker tests? What is the distinction for patients with SCLC?

So, in lung cancer, we will treat tumors that express high levels of PD-L1 with immunotherapy from the outset. Firstline therapy before patients receive any chemotherapy, because if you have a high PD-L1 score, you’re likely to respond. I would say that for patients that have a PD-L1 score less than 50% tumor, initially, frontline therapy will include immune therapy but likely will also include some chemotherapy.

The one exception might be that if a patient’s tumor expresses PD-L1 at low levels. But TMB at higher levels is a type of cancer that is likely to respond to immunotherapy, and so, either Keytruda alone might be given, or a combination strategy like Opdivo (nivolumab) and Yervoy (ipilimumab) might be given for that type of patient. We would expect a patient who has a high level of PD-L1 or a high TMB to have rapid response after the first couple doses of immunotherapy, and what that means is hopefully declining symptoms, improving energy and improving their ability to go about the things they would like to do. It is important to know that if you have a high level of PD-L1 expression in your cancer, and you’re treated with an immunotherapy, there might be a little higher risk of immune-mediated side effects, but most of those side effects are reversible with steroids.

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