Working It Out: Does Exercise Boost the Effectiveness of Melanoma Treatment?

Source: Memorial Sloan Kettering - On Cancer
Date: 11/05/2020
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Exercise is not just an important part of life for Memorial Sloan Kettering physician-scientist Allison Betof Warner — it’s an important part of her research.

Dr. Betof Warner, a medical oncologist who specializes in treating people with melanoma, is also a member of MSK physician-scientist Jedd Wolchok’s lab. There, she studies the effects of exercise on melanoma and other cancers using mouse models. She hopes to eventually apply her findings to her patients.

In an interview, she talked about her work.

How did you get interested in studying the connection between exercise and cancer outcomes?

I’m a lifelong athlete. I was a competitive gymnast for many years, including as a Division 1 student-athlete in college. When I got to medical school [at Duke University School of Medicine], I became a marathon runner and CrossFit athlete. I competed in the CrossFit Games (the world championships of the sport) and have coached CrossFit since 2010.

I was also working on a PhD in cancer biology. I started out studying the structure of tumor blood vessels. Then I heard a talk from Lee Jones about exercise and cancer. [Dr. Jones, who was then at Duke, now leads MSK’s Exercise Oncology Service, which is studying how exercise affects cancer outcomes through both lab research and clinical trials.]

Lee was using mice to study whether exercise could help improve outcomes in breast cancer. He co-mentored me during my PhD, and we published a study that showed exercise improves the quality of the blood vessels going to a tumor, which, in turn, makes chemotherapy more effective.

How has the view of exercise and cancer changed?

When I started my PhD research about fifteen years ago, some people were concerned that if you improved the structure of the blood vessels in a tumor, it might help the tumor grow faster or make it easier to spread. Our research in mice showed that this is not a concern. We still haven’t shown that patients experience all the benefits we’ve seen in mice, but collectively the data suggest that exercise is not harmful — either in melanoma or any other kind of cancer.

Research has demonstrated that exercise has many benefits for people with cancer, including reducing cancer-related fatigue. It also provides psychological benefits by improving overall mood and sense of well-being.

What are you studying now?

My current research has been looking at mice running on a treadmill to see how it affects the immune system — both the immune cells coming into the tumor and those circulating in the body. We’re still learning, but early work has suggested that exercise slows the growth of melanoma tumors in mice and that it does so by acting on the immune system.

I first became interested in this topic when I was a medical resident, and immunotherapy was becoming an important form of cancer treatment. We’ve known for some time that exercise has effects on the immune system, so it raised interesting questions about the role exercise plays in the effectiveness of immunotherapy. After I came here as a fellow, I joined Jedd’s lab, where they were doing research on how to make immunotherapies more effective.

Does your research influence what you tell your patients?

Currently, we don’t have enough data to recommend one particular type of exercise over another. Several organizations, including the American College of Sports Medicine, have put out recommendations for people with cancer that recommend 150 minutes a week of moderate exercise or 75 minutes a week of more vigorous exercise. I share those guidelines with my patients.

If patients were exercising before their cancer diagnosis, I tell them to maintain what they were doing. For people who were completely sedentary, there is no magic number or exercise prescription for me to give them that’s data driven right now. But we know that getting up, moving around, and being active is good for people with cancer, and I tell them that.

What do you do to stay fit these days?

I exercise six days a week. It not only keeps me healthy, but it keeps me sane.

Before the COVID-19 pandemic, I was teaching CrossFit. I got a Peloton bike right before all the gyms closed, and I’ve become an avid user. My husband and I just bought a house in the suburbs, and I’m putting in a CrossFit gym in our garage. He’s very tolerant!

What are your plans for your research?

In addition to continuing my research in the lab, I’m working with Bill Tap [Chief of the Sarcoma Medical Oncology Service] and Julia Glade Bender [Vice Chair for Clinical Research in the Department of Pediatrics], who are leading the new Adolescent and Young Adult program at MSK. [This program aims to meet both the medical and psychosocial needs of people with cancer who are in their teens, 20s, and 30s.] I’m leading the development of an exercise component. It will focus on research as well as clinical care for patients in the program.

Because of the pandemic, the program will be remote at first, but our goal is to eventually hold in-person classes. One thing that’s important to emphasize about exercise is that it helps to create communities. For adolescent and young adult patients, we expect this program will become part of their support system.

MSK Study Is the First to Link Microbiota to Dynamics of the Human Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 11/25/2020
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In recent years, the microbiota — the community of bacteria and other microorganisms that live on and in the human body — has captured the attention of scientists and the public, in part because it’s become easier to study. It has been linked to many aspects of human health.

A multidisciplinary team from Memorial Sloan Kettering has shown for the first time that the gut microbiota directly shapes the makeup of the human immune system. Specifically, their research demonstrated that the concentration of different types of immune cells in the blood changed in relation to the presence of different bacterial strains in the gut. The results of their study, which used more than ten years of data collected from more than 2,000 patients, is being published November 25, 2020, in Nature.

“The scientific community had already accepted the idea that the gut microbiota was important for the health of the human immune system, but the data they used to make that assumption came from animal studies,” says Sloan Kettering Institute systems biologist Joao Xavier, co-senior author of the paper together with his former postdoc Jonas Schluter, who is now an assistant professor at NYU Langone Health. “At MSK, we have a remarkable opportunity to follow how the composition of the microbiota changes in people being treated for blood cancers,” Dr. Xavier adds.

A Unique System for Studying Changes in the Body

The data that were used in the study came from people receiving allogeneic stem cell and bone marrow transplants (BMTs). After strong chemotherapy or radiation therapy is used to destroy cancerous blood cells, the patient’s blood-forming system is replaced with stem cells from a donor. For the first few weeks until the donor’s blood cells — including the white blood cells that make up the immune system — have established themselves, the patients are extremely vulnerable to infections. To protect them during this time, patients are given antibiotics.

But many of these antibiotics have the unwanted side effect of destroying healthy microbiota that live in the gut, allowing dangerous strains to take over. When the patient’s immune system has reconstituted, the antibiotics are discontinued, and the gut microbiota slowly starts to grow back.

“The parallel recoveries of the immune system and the microbiota, both of which are damaged and then restored, gives us a unique opportunity to analyze the associations between these two systems,” Dr. Schluter says

A Years-Long Effort to Find Answers

For more than ten years, members of MSK’s BMT service have regularly collected and analyzed blood and fecal samples from patients throughout the BMT process. The bacterial DNA were processed by the staff at MSK’s Lucille Castori Center for Microbes, Inflammation, and Cancer, which played a key role in creating the massive microbiota dataset. “Our study shows that we can learn a lot from stool — biological samples that literally would be flushed down the toilet,” Dr. Xavier notes. “The result of collecting them is that we have a unique dataset with thousands of datapoints that we can use to ask questions about the dynamics of this relationship.”

This wider effort has been led by Marcel van den Brink, Head of the Division of Hematologic Malignancies, and a team of infectious disease specialists, BMT doctors, and scientists. “For a fair number of patients, we collected daily samples so we could really see what was happening day to day,” Dr. van den Brink says. “The changes in the microbiota are rapid and dramatic, and there is almost no other setting in which you would be able to see them.”

Previous research using samples collected from this work has looked at how the gut microbiota affects patients’ health during the BMT process. A study published in February 2020 reported that having a greater diversity of species in the intestinal microbiota is associated with a lower risk of death after a BMT. It also found that having a lower diversity of microbiota before transplant resulted in a higher incidence of graft-versus-host disease, a potentially fatal complication in which the donor immune cells attack healthy tissue.

New Clues about a Complicated Relationship

The databank that the MSK team created contains details about the types of microbes that live in the patients’ guts at various times. The computational team, including Drs. Schluter and Xavier, then used machine learning algorithms to mine electronic health records for meaningful data. The data from the health records included the types of immune cells present in the blood, information about the medications that patients were given, and the side effects patients experienced. “This research could eventually suggest ways to make BMTs safer by more closely regulating the microbiota,” Dr. van den Brink says.

Analyzing this much data was a huge undertaking. Dr. Schluter, who at the time was a postdoctoral fellow in Dr. Xavier’s lab, developed new statistical techniques for this. “Because experiments with people are often impossible, we are left with what we can observe,” Dr. Schluter says. “But because we have so many data collected over a period of time when the immune system of patients as well as the microbiome shift dramatically, we can start to see patterns. This gives us a good start toward understanding the forces that the microbiota exerts on the rebuilding of the immune system.”

“The purpose of this study was not to say whether certain kinds of microbes are ‘good’ or ‘bad’ for the immune system,” Dr. Xavier explains, adding that this will be a focus of future research. “It’s a complicated relationship. The subtypes of immune cells we would want to increase or decrease vary from day to day, depending on what else is going on in the body. What’s important is that now we have a way to study this complex ecosystem.”

The researchers say they also plan to apply their data to studying the immune system in patients receiving other cancer treatments.

One by One: Single-Cell Analysis Helps Map the Cancer Landscape

Source: Memorial Sloan Kettering - On Cancer
Date: 06/28/2018
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The composition of malignant tumors is incredibly complex. They contain not only cancer cells but also dozens of other cell types, such as supportive tissues, fat, and many kinds of immune cells. These other cells interact with the cancer cells and one another to influence how tumors behave.

To get to the bottom of what drives a tumor’s growth and to find ways to stop it, scientists need to be able to figure out what all these types of cells are and figure out how they work together. Two new studies from Sloan Kettering Institute investigators published today in Cell represent important steps in that direction. One classified the different kinds of immune cells found in breast cancer tumors. It was the largest study of its kind so far. The other took a more fundamental tack. It established a new mathematical framework for extracting as much information as possible from a tumor’s makeup.

“These studies are focused on efforts to look at tumors at the level of each individual cell,” says Dana Pe’er, Chair of SKI’s Computational and Systems Biology Program and senior author of both papers. “Without going down to the level of single cells, we aren’t fully able to understand what’s going on and what is driving a particular cancer.”

A Growing Field Seeks to Map Cancer

The field of single-cell analysis has expanded greatly in recent years. This is due in large part to rapid technological advances. Mathematical and computational techniques now make it possible to sort the huge quantities of data that are generated by these analyses.  

The Human Cell Atlas brings together investigators from all over the world to create a comprehensive reference map of all human cells. Dr. Pe’er, who co-chairs one of this project’s analysis working groups, says the effort has the potential to impact the understanding of many diseases, not just cancer. Collaborative endeavors like this, she notes, can answer fundamental questions about human development.

One of the primary tools in this field is a genomic analysis technique called single-cell ribonucleic acid sequencing (RNA-seq). This system looks at RNA rather than DNA. It enables investigators to determine which genes are expressed, or “turned on,” in particular cells, rather than just which genes are present in the DNA. Because every cell in the body contains the same DNA, RNA analysis provides much-needed detail about cell function and activity.

Characterizing the Immune Landscape of Breast Cancer

One of the new papers is a collaboration among SKI computational biologists and immunologists as well as Memorial Sloan Kettering’s breast cancer team. The study looked at cells taken from human breast tumors. The team also considered normal breast tissue, blood, and lymph node tissue. The investigators analyzed 45,000 immune cells taken from eight tumors and 27,000 additional immune cells.

Identifying such a large number of immune cells could explain why immunotherapy doesn’t always work the same way in each person. Immunotherapy harnesses the power of the body’s natural immune response to fight cancer. Some types of immune cells attack cancer, while others protect tumor cells from harm.

“One of our major findings was that there was a much greater diversity in the states of immune cells found in tumors compared with what we found in normal tissues,” says Alexander Rudensky, Chair of SKI’s Immunology Program and co-senior author of the breast cancer study. A cell’s state is based on not only what type of cell it is but also other factors, such as its location, size, and structure.

“We were surprised to find that, rather than distinct differences between tumor and nontumor tissue, there was a gradient in the levels of different immune cell states,” he says.

In other words, they found a range of differences in the immune makeup of these tissues, not a clear line between the immune cells present in cancer and normal tissue. “This helps explain why tumors have a range of behaviors — not all tumors respond in the same way to immunotherapy,” adds Dr. Rudensky, who is also a Howard Hughes Medical Institute investigator. “But at the same time, we saw common features among the breast cancer samples that were not seen in the normal tissues. From this work, we can start to think about how to develop immunotherapy that’s custom-built for people based on their individual tumor microenvironment.”

Dr. Rudensky explains that the focus on breast cancer was only a starting point to see if the approach would work. The researchers have plans to expand this research to many other types of cancer. “Until very recently, analyzing the data from thousands of cells at the same time would have been a major undertaking,” he says. “But thanks to the transformative work that’s been done by Dr. Pe’er’s team, we can start to grow this area of immunology research.”

Uncovering Hidden Data with MAGIC

The other Cell paper concentrates on identifying the differences among cancer cells themselves, rather than looking at immune cells in their midst. A culmination of five years of work from Dr. Pe’er, the study focuses on cutting-edge ways to reduce the high levels of noise and highlight the biological trends that come from such large quantities of data.

Dr. Pe’er compares the challenge to a common event on crime shows like CSI, in which an image from a photograph is too blurry to make out. “The detectives bring in an expert who has created a computer algorithm to analyze the pixels, allowing them to clearly read the letters and numbers on a license plate,” she says. “In the same way, we have developed a way to reduce the fuzziness in our data and see clear patterns.”

Dr. Pe’er’s collaborators included Smita Krishnaswamy, a former postdoctoral fellow in her lab who now leads her own lab at Yale University. The team dubbed the technique MAGIC for Markov affinity-based graph imputation of cells. The algorithm can recover gene expression data that may be missing from an individual cell if not all of the RNA has been captured.

“Cancer cells have a range of activities. The ones that have the ability to outsmart drugs or to spread to another part of the body are actually quite rare,” she concludes. “Only by looking at the tumor with single-cell resolution are we able to identify them and study them, enabling us to get to the bottom of what gives them these capabilities.”

Putting the STING in Immunotherapy: Research Focuses on Ways to Improve Cancer Treatments

Source: Memorial Sloan Kettering - On Cancer
Date: 09/19/2018
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Drugs called immune checkpoint inhibitors have made a significant difference for some people with cancer. They work by taking the brakes off the immune system, allowing white blood cells called T cells to attack a tumor.

For this approach to work, however, the T cells need to be able to see the tumor and recognize it as something that doesn’t belong in the body. Often, they cannot. That explains why, for most people, these drugs are not effective. Finding new tactics for making tumors more noticeable to the immune system is an important area of research.

Tumors are sometimes described as “hot” if they show signs of inflammation, with lots of immune activity around them. “We’re looking for ways to turn a cold tumor into a hot tumor,” says Memorial Sloan Kettering physician-scientist Liang Deng. “If you can bring the tumor out of hiding and make it more visible, it will help to really ramp up the immune response.”

Finding Ways to Trick Cancer Cells

One approach that many investigators around the world are studying is the potential to harness the cGAS/STING pathway. (The abbreviation cGAS/STING is a much shorter way of saying “cyclic GMP-AMP synthase/stimulator of interferon genes.”)  

In particular, cGAS/STING works by detecting bits of DNA from bacteria or viruses that have infected a cell. The detection fires up the innate immune pathway, the system of immune defenses that are present from birth and are always active. Innate immune cells produce chemicals that alert other parts of the immune system to the presence of the intruders. In 2013, Sloan Kettering Institute structural biologist Dinshaw Patel published two papers in Cellshowing some of these complex structures for the first time.

Now, some pharmaceutical companies are starting to develop drugs called STING agonists. These are small molecules designed to activate the STING pathway after being injected into a tumor, which sends out a beacon for immune cells to follow. The idea is to use these new drugs in combination with checkpoint inhibitors.

“STING agonists are based on the hypothesis that you can trick immune cells into thinking that the tumor cells are infected with a virus,” says MSK physician-scientist Samuel Bakhoum. “Then the immune cells will come in and basically clear the cancer away.”

Seeing the Full Immune Picture

More recently, however, investigators have learned that in some cases the STING pathway plays a role in helping cancers thrive, making this approach more complicated. “It turns out that many cancer cells also have DNA where it doesn’t belong. Rather than being only inside the nucleus where it normally resides, it’s also floating around inside the cytosol [fluid] of the cell. This is caused by a phenomenon called chromosomal instability — a widespread feature of human cancer,” Dr. Bakhoum says.

“Chromosomally unstable cancer cells have found ways to adapt to that floating DNA. They avoid the harmful consequences of cGAS/STING activation while using this pathway to their advantage,” he adds. “Alternatively, a small number of tumors lose cGAS and STING altogether. This adaptation to DNA in the cytosol may actually help them spread to other parts of the body.” In January 2018, Dr. Bakhoum was the first author of a paper in Naturethat reported this phenomenon.

Along with researcher Lewis Cantley of Weill Cornell Medicine, Dr. Bakhoum recently published a review article in Cell on the ways that cells with unstable chromosomes use STING to their advantage to evolve and become more aggressive. It turns out that chronic activation of this pathway might suppress the immune system rather than trigger it to fight the cancer. “It suggests that we need to be very careful in determining which people could benefit from treatment with STING agonists,” Dr. Bakhoum says. “Patient selection will be a critical contributor toward the success of this therapy.”

Another Approach to Heating Up Tumors

Dr. Deng’s lab is taking a different tack for activating innate immunity in tumors: injecting them with a virus. This is another way to flag tumors and make them more visible to the immune system.

She’s working with modified vaccinia virus Ankara (MVA). This engineered virus has been safely used as a vaccine against smallpox. In 2017, her laboratory published a paper in Science Immunology demonstrating that injecting inactivated MVA into tumors in mice stimulates the immune response against the tumors. The findings showed that the response was boosted by checkpoint inhibitor drugs.

Now her laboratory is working on engineering MVA to make it more potent for immunotherapy. Dr. Deng explains that using the engineered MVA has several potential advantages over drugs designed only to fire up STING. For one thing, the virus is larger than a drug molecule, allowing it to remain in the tumor tissue for a longer time. In addition, the virus can be engineered to do much more than draw attention to the tumor.

The engineered MVA activates STING not only in tumors but T cells too. It also carries a growth factor for immune cells called dendritic cells. “We know based on previous work that dendritic cells are an important part of the immune response to cancer,” she says. “Injecting engineered MVA into tumors creates an in situ vaccination effect, which teaches T cells to recognize tumors.”

Dr. Deng and her MSK colleagues Jedd WolchokTaha Merghoub, and Stewart Shuman recently co-founded a start-up company called IMVAQ Therapeutics. The company is developing the virus so that an application can be submitted to the US Food and Drug Administration to begin clinical trials. IMVAQ is planning tests in a number of solid tumors, either alone or in combination with checkpoint inhibitors. “We hope this approach will be particularly successful in tumors that don’t usually respond to checkpoint inhibitor drugs, like breast and prostate cancers,” she notes. “We also believe this virus will be very safe because it doesn’t replicate in human cells.”

MVA is not the only virus being studied for this purpose. MSK already has other trials underway that use this immunotherapy approach as well. A phase III trial using a virus called T-VEC (talimogene laherparepvec) is being studied in combination with the checkpoint inhibitor pembrolizumab (Keytruda®) for advanced melanoma, for example.

“All of the research that’s been done over the past 20 years on the basic science of the innate immune system, including a lot of work done at MSK, has made these kinds of studies possible today,” Dr. Deng concludes.

Researchers Identify a Bacterial Species That Could Protect against Hospital-Acquired Infections

Source: Memorial Sloan Kettering - On Cancer
Date: 08/21/2019
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Hospital-acquired infections are a major threat, especially for people whose immune systems may be compromised because of cancer treatment. In recent years, researchers have been studying fecal microbiota transplants as a way to treat this serious complication. These transplants involve collecting stool from a healthy donor and delivering it into the intestine of the patient. The beneficial microorganisms from the transplant restore the balance of healthy bacteria in the gut.

Little is known, however, about which species of bacteria offer protection against harmful pathogens or exactly how they provide this benefit. A new study from Memorial Sloan Kettering is reporting the first evidence of a bacterial species that appears to maintain the balance of healthy microbes by killing dangerous ones. The findings also suggest how it mounts this attack. The research was reported August 21 in Nature.

“A lot of work is being done to figure out how harmful pathogens are able to colonize the human body,” says first author Sohn Kim, an MD-PhD student in the Tri-Institutional MD-PhD Program of MSK, Weill Cornell Medicine, and The Rockefeller University. “This project provides important new information about the bacteria that keep them in check.”

Focus on a Deadly Infection

The study focused on a particularly threatening hospital-acquired infection called vancomycin-resistant Enterococcus (VRE). VRE sickens about 20,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and kills up to 10% of them. Earlier work led by former MSK graduate student Silvia Caballero, a co-author on the current study, showed that a mixture of four bacterial strains protect lab mice from VRE. These strains are normally found in the gastrointestinal tracts of healthy people.

The new study built on this earlier work by conducting a series of experiments to isolate one of these four bacterial strains: Blautia producta. “The next step was to determine the mechanism by which Blautia producta mediates protection against VRE,” Dr. Kim says. It turned out that a protein produced by Blautia producta is able to kill VRE even when the bacterial cells themselves aren’t present. Further study revealed that this protein is a lantibiotic, a type of antibiotic that is manufactured by microorganisms.

“If you think of Blautia producta as a member of the microbiota that helps maintain order within the gut, this lantibiotic is what it uses to do that,” says MSK infectious diseases expert Ying Taur, a co-author on the study. “This study really helps further our understanding of how all this works and provides important new insight.”

Evaluating the Effects of a Bacterial Product

The researchers did a number of additional studies. These included sequencing the gene that codes for the lantibiotic and performing RNA sequencing to determine when the gene is expressed.

They also tested the lantibiotic against about 150 strains of intestinal bacteria, to gain a sense of its spectrum of activity. This part of the research was significant because a major side effect of the antibiotics that doctors prescribe is that they can wipe out these healthy strains.

The team found that Blautia producta and the lantibiotic did not damage healthy strains. In fact, when they reviewed their library of samples collected from healthy donors, the researchers learned that about half of them already had Blautia producta and this lantibiotic product.

“It’s remarkable how precise this product is at targeting harmful microbes while sparing healthy ones,” Dr. Taur notes. “This is something we do not know how to do with any antibiotics that we have now. Our antibiotics are very clunky in comparison to the precision of what these bacteria do.”

Moving Forward with More Research

More work is needed before this approach can be tested in people with VRE infections. Drs. Kim and Taur say they haven’t even determined how a treatment would be best administered or whether they would use Blautia producta or the isolated lantibiotic. The treatment could possibly be given as a pill, or the findings from this study could be used to develop a more specialized type of fecal microbiota transplant. They plan to study various approaches in mouse models.

“Previously, studies have shown that Blautia is associated with better outcomes in people who have developed graft-versus-host disease (GVHD) after having a bone marrow transplant with donor cells,” says study co-author Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “In addition, we have recently found that Enterococcus is associated with increased incidence of GVHD. These findings offer exciting opportunities to control GVHD and improve outcomes for people having transplants.”

“There are a lot of things we still don’t know, but we have learned so much from this study,” Dr. Taur concludes. “It was really an amazing piece of detective work.”

Clinical and Basic Research from the Brigham Highlighted at Annual ACR Meeting

Source: Brigham and Women's Hospital - On a Mission
Date: 01/17/2020
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This November, members of Brigham and Women’s Hospital’s Division of Rheumatology, Inflammation and Immunity presented several groundbreaking studies at the American College of Rheumatology’s (ACR’s) annual meeting in Atlanta.

Among the work presented was clinical research examining avoidable health problems in Medicaid recipients with lupus and basic research focusing on single-cell analysis of immune cells from various autoimmune disease tissues.

Preventive Care in Low-Income Lupus Patients

The lupus study was led by investigator and clinician Candace H. Feldman, MD, MPH, ScD. She and her colleagues used billing claims data for Medicaid beneficiaries to look at vaccine-preventable illnesses for which lupus patients end up in the emergency room or hospital. They found a significant burden of acute care use for these conditions that could be prevented with vaccines.

Many lupus patients have difficulty accessing outpatient care, where most preventive services are provided. Obstacles include transportation problems, an inability to miss work due to financial constraints and a lack of childcare. Dr. Feldman noted that she and colleagues focused on conditions that would be potentially avoidable or whose harm or adverse events would be lessened through sustained access to high-quality outpatient care.

According to Dr. Feldman, studies have shown that lupus patients tend to have low rates for several vaccines, including human papillomavirus (HPV), influenza and pneumococcal disease. “Also, compared with the general population, people with lupus are more susceptible to infections both from the disease itself and from the medications that suppress their immune system and are more likely to have severe complications if they develop these infections,” she added.

One reason vaccines may be overlooked, Dr. Feldman explained, is that patients with complicated illnesses usually have a number of other things to discuss during clinic visits. She pointed out that a few studies, mostly case reports, have suggested that vaccines may be unsafe for people with autoimmune diseases like lupus, but stressed that larger studies have refuted these findings and confirmed that these non-live vaccines are both safe and efficacious for most patients with lupus.

“Another issue is that many people with lupus, especially younger patients, tend to get much of their primary care from rheumatologists. Yet rheumatologists may not be thinking about whether their patients need these vaccines or stock them in their clinics or be equipped to provide preventive care like pap tests,” Dr. Feldman said. “It’s important that rheumatologists be aware of these issues and talk to their patients about vaccinations and other forms of preventive care.”

Immune Cell Subtypes Across Many Inflammatory Diseases

The single-cell analysis study included an in-depth examination of immune cells from people with immune dysfunction, such as rheumatoid arthritis, lupus nephritis, ulcerative colitis, Crohn’s disease and interstitial lung disease. All samples were from human tissues and compared to tissues of the same type taken from noninflammatory or health samples.

“Traditional bulk RNA sequencing provides average quantifications of gene expression across different populations of cells. Recent advances of single-cell technologies have provided single-cell transcriptomics to unbiasedly uncover diverse immune cell populations from disease tissues,” said Fan Zhang, PhD, a computational biologist at the Brigham, Harvard Medical School and the Broad Institute of Harvard and MIT, who presented the work at ACR. “Single-cell analysis gives us a much higher resolution and allows us to quantify many finer immune subtypes and their contributions to disease pathogenesis in each individual sample.”

The data used in this study came from several publicly available datasets, including the single-cell data generated by the Accelerating Medicines Partnership RA/SLE consortium, which is funded by the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases and several pharmaceutical companies.

“Many researchers have done immunogenomics research with a focus on only a preselected cell type and one immune dysfunction disease,” Dr. Zhang said. “Something that was unique about our study was that we compared multiple immune cells from similar inflammatory diseases from different tissues and organs. Thus, there was obviously a computational challenge that required a lot of multidata integration as well as an understanding of immunology and rheumatology.”

The investigators identified 21 diverse cell-type populations across multiple tissue sources, including distinct subpopulations of myeloid cells, T cells, B cells and plasma cells.

“Our research showed what these diseases have in common and also what’s different about them,” Dr. Zhang said. “They suggested new approaches for common therapeutic drugs based on the shared inflammatory immune cells, which may be effective for a number of different autoimmune diseases. I think integration of computational biology and immunogenomics with the field of rheumatic diseases is promising and will generate new insights for drug discovery.”

Deep Understanding of Immunotherapy Helps Patients Cope with Side Effects

Source: Memorial Sloan Kettering - On Cancer
Date: 04/16/2020
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Immunotherapy has changed the outlook for many people with cancer. It offers long-term control or even a cure for tumor types that don’t respond well to other treatments. But because immunotherapy works in a different way than more traditional cancer treatments, such as chemotherapy and radiation, it can lead to new kinds of side effects.

Memorial Sloan Kettering is a leader in developing immunotherapy approaches, including drugs called checkpoint inhibitors. These drugs work by taking the brakes off immune cells and allowing them to go after cancer. But sometimes the immune system becomes too active and attacks healthy tissue. This reaction, called an immune-related adverse event, occurs in about one-third of people taking these drugs. As pioneers in immunotherapy, MSK care providers have rich experience in managing and easing these side effects. This enables most people to complete their cancer treatment and increases the chances that it will ultimately be successful. 

The most common immune-related adverse events caused by checkpoint inhibitors are skin problems, such as rashes, and inflammation of the gastrointestinal tract, which causes problems like diarrhea. Less frequent but potentially serious side effects include inflammation in the heart, liver, kidneys, lungs, and endocrine glands. Overactive immune cells can also affect the joints. This can lead to a painful condition similar to rheumatoid arthritis.

A Leader in Clinical Trials

Some of the earliest clinical trials of checkpoint inhibitor drugs were headed by MSK physician-scientist Jedd Wolchok. From the beginning, Dr. Wolchok and his colleagues — including Alyona Weinstein, a nurse practitioner who works in Dr. Wolchok’s clinic — began seeing immune-system reactions in their patients that looked like autoimmune disorders.

“We’ve known for a long time how to manage the most common side effects from chemotherapy,” such as nausea and reduced blood counts, Ms. Weinstein says. But the side effects from checkpoint inhibitor drugs can be more wide-ranging and unpredictable. “The inflammation caused by an overactive immune system can happen in any part of the body,” she notes. “At MSK, we are careful to screen patients for these side effects early in their treatment so that we can manage them before they become serious.”

A Growing Community of Specialists

As more people have received checkpoint inhibitors, a cadre of experts in immune-related side effects has naturally grown within MSK’s Division of Subspecialty Medicine. Specialists include dermatologists, gastroenterologists, cardiologists, endocrinologists, and more. They focus on health problems other than cancer. But because they work at MSK, they exclusively treat these disorders in people with cancer.

“When patients see the list of potential side effects, they often get very worried,” Ms. Weinstein says. “But in many cases, the appearance of these side effects is an early indication that the drugs are working.” She adds that while some people have no side effects, others may experience more than one serious complication. 

“The management of side effects requires supportive services from many areas beyond medical oncology, and MSK has these specialists,” says Michael Postow, a medical oncologist who specializes in immunotherapy. “Our doctors see these problems a lot, and they’ve developed deep expertise within their areas of specialization.”

Focusing on Health and Quality of Life during and after Treatment

MSK dermatologist Mario Lacouture treats people with skin-related side effects from immunotherapy and other cancer treatments. He recently received a five-year grant from the National Institutes of Health to study the immune-system-related side effects of immunotherapy. The project is a collaboration with National Jewish Health in Denver, a leading center for immunological disorders.

“The big dilemma is that you want to suppress the side effects of immunotherapy enough that patients feel well but not enough that the cancer therapy is no longer active or that patients have additional side effects from immunosuppressive drugs,” Dr. Lacouture explains. “We plan to use the skin as a model to identify what causes these autoimmune reactions so we can develop better ways to treat side effects without reducing the effectiveness of the cancer treatment.”

Other MSK specialists who play a role in treating autoimmune side effects include gastroenterologist David Faleck, cardiologist Dipti Gupta, and endocrinologist Monica Girotra. MSK’s team also closely collaborates with specialists at other area hospitals. This includes rheumatologists at the Hospital for Special Surgery, who are studying arthritis caused by checkpoint inhibitors and treat many of MSK’s patients.

Physical and occupational therapists, as well as specialists in integrative medicine, can help patients cope with pain and mobility problems. Because the gastrointestinal side effects from checkpoint inhibitor drugs can be difficult to treat with medication alone, MSK also has nutritionists who can advise people about the best diets for reducing symptoms related to these complications.

“Our hope is that our patients live a long time, and we know that, unfortunately, autoimmune side effects can continue even after they finish their treatment,” Ms. Weinstein concludes. “We are focused on making sure our patients have a good quality of life in addition to successful treatment for their cancer.”

Research Uncovers Details about How Gut Microbes Influence the Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 04/22/2020
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The microscopic organisms that live in our intestines perform many jobs to keep us healthy, such as helping our bodies digest nutrients from food. They keep harmful microbes under control and prevent them from taking over the gut, and also play a role in regulating the immune system.

Researchers at Memorial Sloan Kettering are studying the connections between gut microbes and human health. In a study published April 15 in Nature, an MSK team uncovered new findings about an important relationship: the way that gut microbes promote the formation of a type of immune cell called regulatory T cells (Tregs).

Tregs help keep powerful immune responses in check. They are crucial for preventing autoimmunity, when the immune system mistakenly attacks the body. Tregs also play a role in cancer: Cancer is more likely to develop when malfunctioning Tregs lead to chronically inflamed tissue. This is seen in conditions such as inflammatory bowel disease (IBD).

Focusing on the Microbe–T Cell Connection

“Life in all mammals, including humans, is impossible without regulatory T cells,” says the study’s senior author, Alexander Rudensky, Chair of the Immunology Program in the Sloan Kettering Institute and a Howard Hughes Medical Institute investigator. “This study builds on previous research from our lab and others that looked at how these cells are made and why they are so important.

“It’s already been shown that disturbance of the microbial community in the gut is associated with autoimmune and inflammatory diseases, like IBD,” he adds. “These findings have illustrated the importance of the relationship between the microbes that live in our guts and our immune systems.”

To better understand this relationship, Dr. Rudensky and his team study how different microbes in the gut affect the production of Tregs that protect against inflammation and autoimmune conditions. They do this by looking at the molecules that microbes make to carry out their metabolic functions. Then they study how those metabolites in turn influence the manufacturing of Tregs.

In the experiments, the investigators concentrated on a class of metabolites called secondary bile acids. These are produced by gut microbes. Bile acids help the digestion of dietary fats.

Members of Dr. Rudensky’s team focused on a type of gut bacteria belonging to a group called Bacteroides and engineered them to produce a particular bile acid, called isoDCA. They exposed naive T cells, which had not yet developed into a specific T cell type, to isoDCA during the process of their activation. They found that isoDCA caused the immature T cells to become Tregs.

Ultimately, these findings could lead to a bacterial-based therapy for the treatment of IBD associated with imbalanced microbes and diminished Treg activity. (Currently, IBD is treated with anti-inflammatory drugs, which can have many side effects.) But Dr. Rudensky says much more work is needed before this kind of treatment could be tested. Many parts of the process are still not well understood. In addition, researchers would have to do extensive testing in mice before designing a clinical trial. “We plan to continue exploring the possibility of using metabolic products from microbes for the treatment of inflammatory disorders,” he says.

The two first authors on the paper were research fellow Clarissa Campbell and research associate Peter McKenney in Dr. Rudensky’s lab. Investigators in MSK’s Donald B. and Catherine C. Marron Cancer Metabolism Center, including the center’s director, Justin Cross, also contributed to the research.

Why Salmonella wants its host to have a healthy appetite

Source: Cell Press
Date: 01/26/17
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Anyone who’s ever had the flu or a bad cold can relate to the lethargy, sleepiness, and an increased sensitivity to pain that often result when a pathogen infects a host. A Salk Institute study, published January 26 in Cell, looked at one of the most well-known sickness behaviors–loss of appetite–in mice and found, surprisingly, that when a bacteria reduces its own virulence (how sick it makes the host) by blocking this anorexic response, it actually increases mouse survival and helps the pathogen spread because more food means more infected feces.

“Traditionally in infectious disease, we think that the stronger a pathogen’s ability is to cause disease, the greater its potential is to be transmitted to other hosts,” says senior author Janelle Ayres, an assistant professor in immunobiology and microbial pathogenesis at the Salk Institute for Biological Studies. “But we discovered a pathogen that has evolved to become less dangerous to its host. By employing this strategy, it’s easier for the pathogen to spread to other hosts.”

In the study, the investigators looked at Salmonella Typhimurium, a natural intestinal pathogen in mice (as well as humans) that can easily be transmitted to new hosts. Previous work looking at the connection between Salmonella and loss of appetite has mostly involved injecting a microbe or microbial products directly into the circulation of an animal model and studying its effect, but Ayres’ group infected the animals orally–thus mimicking the bacteria’s route of infection (it spreads from mouse to mouse when the animals eat each other’s contaminated feces).

“Host response is only half of the infectious disease equation. We wanted to understand how the bacteria’s behavior is affected by the host’s loss of appetite, as well,” Ayres says. “What a pathogen wants is a steady supply of nutrients, a stable niche so it can replicate, and a reliable mode of transmission.” In this case, taming the behavior of the pathogen by enabling the mice to take in more nutrition helped keep the mouse healthy, produce more feces, and then spread infection to other animals.

Further investigation revealed the mechanism by which Salmonella Typhimurium inhibits loss of appetite. Sickness behaviors are in large part mediated by a cytokine–a type of molecule involved in cell-to-cell communication–that sends a signal to the hypothalamus, a region of the brain controlling appetite. But this particular Salmonella blocks activation of the cytokine in the intestines, preventing the gut from signaling to the brain.

Ayres says she anticipates finding a similar strategy in other microbes, noting that genes similar to the one known to be important in blocking cytokine activation in SalmonellaTyphimurium also are found in other pathogens. “But a more interesting place to look is at the components of the microbiome, especially the human microbiome,” she notes.

“When an infection in the host affects appetite, the microbiome is also potentially compromised by the loss of nutrition. I expect to find that the microbiome has evolved strategies to block this sickness response,” Ayres adds.

This is something her research group plans to study.

The researchers hope that one day, their findings may lead to a better understanding of infection transmission and new ways to treat infections by supplementing patients with nutrition rather than treating them with antibiotics. The goal would be to give patients a treatment that would also prevent them from spreading their cold or fever to others.

Newly discovered gut organism protects mice from bacterial infections

Source: Cell Press
Date: 10/06/16
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While bacteria are often stars of the gut microbiome, emerging research depicts a more complex picture, where microorganisms from different kingdoms of life are actively working together or fighting against one another. In a study published October 6 in Cell, scientists reveal one example: a newly discovered protist that protects its host mice from intestinal bacterial infections.

“This was a serendipitous finding, but an important one,” says senior author Miriam Merad, a Professor of Oncological Sciences and of Medicine at the Icahn School of Medicine at Mount Sinai. “This study shows how vital it is to go beyond bacteria when studying the microbiome.”

The investigators made the discovery when they realized that mice that had been bred at their own facility had a greater number of immune cells in the gut than mice purchased from an outside vendor. Graduate student Aleksey Chudnovskiy, the study’s first author, together with postdoctoral fellow Arthur Mortha, decided to figure out why that was the case. When they performed an intestinal cleanse on the two groups of mice, they were surprised to find that the mice from the Mount Sinai facility had flagellated protozoa living in their guts. DNA sequencing revealed that the microorganism was a new protozoan parasite, which they named Tritrichomonas musculis (T. mu).

Further investigations showed that when this protist was given to the mice that didn’t have it, they, too, had an increase in the number of immune cells in their guts and also increased inflammatory cytokines. The researchers set out to discover the underlying mechanism. They found that T. mu activates the inflammasome in the gut epithelial cells of the mice, which in turn led to the activation of cytokines. They also found that dendritic cells were required to induce inflammation.

To determine whether colonization of T. mu in the gut affected the mice’s ability to fight off infection, they infected mice with Salmonella and found that the animals that had T. mu as part of their microbiome were very resistant to Salmonella infection. “The protective effect of this species is very striking,” Chudnovskiy says.

T. mu was found to be an ortholog of Dientamoeba fragilis, a parasite that’s found in the guts of many humans, but the researchers don’t know if D. fragilis also has a protective effect. It’s something they plan to study. “People from industrialized countries traveling to emerging countries are more susceptible to intestinal infection than the indigenous population,” Merad explains. “It’s possible that protists, which are known to be common in emerging countries, contribute to the protective effect against intestinal pathogenic infections.”

She adds: “The fight against pathogens determined the survival of the human species, and those with stronger immune systems are the ones who survived. It is likely that the microbiome is a big part of the evolutionary process. Thus, identifying those commensals that confer immune strength in exposed communities should help identify novel therapeutics.”