Examining the Effects of Immunotherapy on Cancer

Using a collection of sophisticated single-cell technologies, scientists at the Mount Sinai Health System have launched an early-stage clinical trial that examines the effects of immunotherapy on hepatocellular carcinoma, non-small-cell lung cancer, and head and neck squamous cell carcinoma.

Four to six weeks before a tumor is resected, the researchers administer a neoadjuvant immunotherapy, cemiplimab, and study its effects. As soon as the tumor is removed, they continue to analyze the fresh tissue for a month or more to observe mechanisms of resistance and response. The Phase 1 trial is sponsored by Regeneron Pharmaceuticals, Inc.

“With the technologies available to us at The Tisch Cancer Institute and Mount Sinai’s Human Immune Monitoring Center, we are able to investigate at an unprecedented depth how these immune therapies are changing the microenvironment within the tumor,” says Thomas Marron, MD, PhD, Assistant Professor of Medicine (Hematology and Medical Oncology), Icahn School of Medicine at Mount Sinai, and Principal Investigator of the study. “This trial enables us to analyze fresh tissue immediately after resection—instead of the preserved tissue typically obtained in trials—to observe the dynamic changes that occurred.”

The study is enrolling multiple small cohorts of 21 patients. One goal is to determine which cancer patients will benefit from cemiplimab, and, more specifically, how cemiplimab can be more effective by combining it with chemotherapy and/or other novel immunotherapies. Cemiplimab was previously studied at Mount Sinai in liver and lung cancer patients and has been approved by the U.S. Food and Drug Administration for patients with metastatic cutaneous squamous cell carcinoma. The compound works by inhibiting the interaction between PD-L1, a protein on the surface of tumor cells, and PD-1, the protein on the surface of T cells, and restoring the immune system’s ability to recognize and kill cancer cells.

Another goal of the study is to identify biomarkers in human tissue and blood that will be able to predict who will respond to immunotherapy, since so many patients do not respond to anti-PD-1 therapy. “We really need to find the ideal patients to treat so we don’t unnecessarily expose those who won’t respond to the toxicity of immune therapies,” says Dr. Marron, who is also Assistant Director of Early Phase and Immunotherapy Clinical Trials at Mount Sinai. “There’s also a financial issue at stake for patients and society in general in using expensive drugs that are not improving outcomes.”

Dr. Marron and his team are using several powerful new technologies to help them with their work. These include immune mapping and monitoring technologies such as mass cytometry (CyTOF), a flow-cytometry-like technology that allows them to see up to 50 proteins on each cell so they can identify the cell type and classify the maturation and activation status of the cell, along with some of the regulatory “on/off” checkpoints.

CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) is another platform that provides an even higher resolution view of each individual cell within the tumor. This technology combines the capabilities of CyTOF and single-cell RNA sequencing to characterize both the RNA and protein in each cell.

A third technology is known as Multiple Ion Beam Imaging (MIBI), a unique form of immunohistochemistry that allows scientists, for the first time, to unravel the spatial architecture of tumors in order to better understand the mechanisms through which the immune system is infiltrating the tumor and is being hijacked by the tumor.

“For 10 years, we’ve been building the Human Immune Monitoring Center into one of the leading platforms in the world for investigating the role of the immune system in human disease, and using that knowledge to design novel, immune-based therapies,” says Miriam Merad, MD, PhD, Director of the Center, and Professor of Oncological Sciences, and Medicine, Icahn School of Medicine at Mount Sinai.

Drawing on a highly specialized team of clinicians, immunologists, mathematicians, physicists, and surgeons, the Human Immune Monitoring Center is currently involved in more than 45 federal- and foundation-funded research programs in fields such as cancer, autoimmune disease, inflammatory bowel disease, allergies, and neurodegenerative disease.

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Targeting regulatory T cells could boost the effects of cancer immunotherapy

A Ludwig Cancer Research study has identified a mechanism by which regulatory T cells, which suppress immune responses, adapt their metabolism to thrive in the harsh microenvironment of the tumor. This mechanism, the study finds, is exclusively engaged by regulatory T cells (T_regs) that reside in tumors and could be disrupted to selectively target such T_regs and boost the effects of cancer immunotherapy.

"It has long been known that the T_regs found in tumors protect cancer cells from immune attack, so countering T_regs would be an important strategy for cancer immunotherapy," says Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research, who led the study. "But a major hurdle to such interventions is that the systemic suppression of T_reg activity can cause severe autoimmune reactions. We have discovered a potential approach to overcoming that problem, one that selectively targets T_regs in tumors and could therefore prevent such adverse effects."

T_regs play a critical role in healthy tissues, where they prevent autoimmune disease and aid wound-healing. But, when recruited into tumors, T_regs also thwart anti-cancer immune responses-;and immunotherapy. The current study, published in Nature Immunology, identifies a protein that drives the metabolic adaptations of intratumoral T_regs. The researchers show in a mouse model of melanoma that targeting that protein with an antibody significantly boosts the efficacy of immunotherapy without causing autoimmune side effects.

The cores of tumors are often acidic and starved of oxygen and vital nutrients, which forces resident cells to adapt their metabolism to survive. Ho and graduate student Haiping Wang suspected those adaptations might also reveal vulnerabilities unique to intratumoral T_regs. To find those vulnerabilities, they analyzed a dataset of T_reg gene expression in breast tumors and blood compiled a few years ago by the laboratory of Ludwig MSK Director Alexander Rudensky.

They found that those and other intratumoral T_regs expressed high levels of genes involved in lipid uptake and metabolism- particularly CD36, a receptor involved in lipid import. An analysis of T_regs from human melanoma patients conducted by Ludwig Memorial Sloan Kettering (MSK) researchers Taha Merghoub and Jedd Wolchok yielded similar results.

To explore the role of CD36 in intratumoral T_regs, the researchers generated mice that lacked the CD36 gene only in their T_reg cells and engrafted them with melanoma. "We found that the tumor burden was reduced in CD36-deficient mice," says Wang, "and the number and functionality of T_regs declined only within tumors, not in the other, healthy tissues of the mice."

CD36 deficiency induced in intratumoral T_regs a form of cell suicide known as apoptosis that was driven by a decline in the health and number of mitochondria-;the power generators of cells. Further study revealed that CD36 fuels the activity of PPARβ, a protein essential to the genesis and function of mitochondria.

Treating mice bearing melanoma tumors with an antibody to CD36 resulted in a decline of intratumoral T_regs that was not seen in genetically identical control mice. When this antibody was combined with an immunotherapy known as PD-1 blockade, which stimulates a T cell attack on cancer cells, tumor growth slowed significantly, prolonging the survival of the mice.

By targeting CD36 with an antibody, we don't just create trouble for intratumoral T_regs, we also createtrouble for the tumor's ability to maintain an immunosuppressive microenvironment and hamper immunotherapy."Ping-Chih Ho, associate member of the Lausanne Branch of the Ludwig Institute for Cancer Research

Ho's lab is now working to translate these findings into a potential cancer therapy while exploring how CD36-targeting might be combined with other interventions to more extensively disable T_regs selectively within tumors. They are also exploring which other types of solid tumors harbor T_regs that are dependent on CD36 for survival.
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7 Discoveries Showing How the Brain and Body are Linked

The brain is a part of our body, so of course, it's connected and influenced by our body, you may think. And while this basic assumption is definitely at the heart of the findings we will discuss here, the ways in which our brains are interconnected with the other organs and systems of our body can be quite unexpected, with things like hydration level and specific foods having a profound influence on our mind. But it isn't only our gut or cardiovascular system that can influence how well our brains work: our experiences and habits are just as important to our mental health and cognitive performance. These 7 neuroscientific discoveries illustrate how our brain, our body, and our experiences are all meaningfully interconnected and have a strong effect on our health and well-being.

1. Your Brain’s Health and Functioning is Dependent on Your Gut Health

The idea of the gut-brain connection has been around for a while, but the more scientists learn about the specific ways our guts influence our brains, the more we get to understand the holistic importance of a healthy diet. More specifically, we now know that a poor diet is a contributor to mental illness, particularly anxiety and depression, but it may also alter our cognitive abilities.

For example, a diet high in sugar was shown to impair our cognitive abilities in the short term, causing brain fog. The long-term effects of sugar are no less alarming, as there is evidence linking depression and a high-sugar diet. On a more positive note, a healthy diet was shown to have a beneficial effect on depression. 

2. Mental Tasks and New Experiences can Boost one’s Brain Health

One of the most significant neuroscience discoveries of the past decade is the idea that our brain is malleable and new experiences, training, and learning can improve its functioning. In neuroscience, this notion is known under the term 'neuroplasticity', and, as you might expect, the human brain is most pliable in childhood, but it continues being shaped by our experiences throughout our lives.

This is why reading, playing and listening to music, painting and many other types of mental training are all so beneficial for our cognitive health and help us maintain a sharp mind for longer. More interestingly, recent scientific research focusing on the ways we can use neuroplasticity to our advantage also showed that we can improve our memory by simply engaging in new enjoyable activities and trying new things. 

3. Both Too Much and Not Enough Sleep Can Affect Your Cognition

Sleep is one of the favorite topics in neuroscience, with numerous studies suggesting that both too much and not enough sleep can impair our memory, creativity and cognitive tasks, such as concentration and problem-solving. The largest-ever sleep study was conducted in 2017, with over 10.000 participants tested, and it concluded that the previous hypothesis was true and sleep does affect our decision-making and concentration even in the short term.

However, the same study concluded that memory performance is NOT affected by sleep, although admittedly they did not look at the long-term effects of sleep. Still, it’s best to get an average 7-8 hours of sleep every day to stay in top shape.

4. Healthy Body, Healthy Mind: the Effects of Exercise on Our Brain

Your brain needs exercise, we discussed that in the second point but turns out that regular old exercise, too, can boost your cognitive health and help retain a sharp mind in your senior years. One study even suggested that exercise helps delay dementia by 15 years!

Apart from being an excellent preventative measure of Alzheimer’s and dementia, however, exercise can help us boost our cognitive performance and thinking skills, too. As for the kind of exercise in question, experts suggest that a mixture of cardio, flexibility training, strength and resistance training will give you the greatest cognitive boost, but as long as you exercise regularly, any training you enjoy will benefit your brain as well.

5. Chronic Stress Can Shrink Your Brain

You probably heard that a little stress is useful for our brain from time to time, and it may be true, but most of us don’t get just a little stressed, don’t we? And that’s exactly the problem. When we are stressed out day after day, our prefrontal cortex, the steering wheel of our brain, gets affected, making us less alert and worse at performing cognitive tasks, all because of cortisol, the infamous stress hormone.

Another brain area affected by stress is the hippocampus, which helps us learn and remember things. Ultimately, chronic stress can even cause mood swings, irritability, mental illness (e.g. anxiety, depression, addiction) and was even found to contribute to Alzheimer’s disease. In extreme cases, constant stress was even shown to be able to shrink the brain volume, particularly the cortex.

6. Mindfulness May Help Keep Your Brain Younger for Longer

Mindfulness training is the hot topic both in psychology and neuroscience nowadays, but it’s not a new invention, as both yoga and meditation rely heavily on the idea of self-awareness and mindfulness. There’s a massive amount of research showing that mindfulness can make you more resistant to pain, help you deal with mental illness and even prevent cortical degeneration caused by dementia and aging.

So if there’s one thing you should start doing, that’s some sort of mindfulness practice, be it yoga, meditation, or mindful breathing.

7. Your Water Intake Affects your Brain

A dehydrated brain is a sluggish brain, one that can make it difficult for you to focus, maintain attention, and engage in problem-solving tasks. A 2018 study found that losing as little as 2% of body weight for adults can instantly affect all these mental faculties. Keep in mind that losing that much water is not uncommon, especially in the summer weather.

Also, kids and seniors are at a higher risk of suffering from dehydration. The conclusion is simple: always keep a full water bottle on hand, especially if you’re spending time in the sun, but don’t overindulge either. Why? This is because drinking too much water is as dangerous as dehydration, as it can dilute your blood and, in severe cases, can make your brain swell, which can be lethal.

How much water should you drink, then? Doctors generally recommend drinking around half a gallon (2 liters) of water a day for an average adult, which is about 8 glasses of water, but this may differ depending on your weight and diet.

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New device shows promise in Type 2 diabetes treatment

Researchers have found that a newly tested medical device, called ‘Sleeveballoon’, mimics the effects of traditional bariatric surgery in rodents and produces impressive results on body weight, fatty liver and diabetes control.

Sleeveballoon is a device that combines a balloon with a connected sleeve, which covers the initial parts of the small intestine. It is inserted into the stomach and bowel during minimally invasive surgery under general anaesthetic.

For the study, researchers compared the effects of the Sleeveballoon and traditional bariatric surgery on 30 rodents fed with a high-fat diet, achieving very similar results.

Results were also compared to rats, with the new device reducing food intake by 60 per cent and resulting in a 57 per cent reduction in fat mass.

The effect on diabetes was similarly impressive with blood glucose levels dropping by 65 per cent.

“Gastric bypass surgery is a highly effective treatment of obesity and type 2 diabetes. However, very few eligible patients, only around one per cent, are offered surgery and some also prefer less invasive approaches,” said study’s lead author.

“However, while gastric bypass causes a rapid rise in post food blood glucose levels which can cause hypoglycaemia, the Sleeveballoon induces a slowing down of digestion which has a steadying effect on blood sugar levels,” the author said.

“This helps control appetite and hunger, keeping the person fuller for longer and substantially reduces weight,” he added.


During the study, the research team found that the metabolic effects of the Sleeveballoon device are similar to those of the gastric bypass but have distinct advantages over the traditional method.
In both, insulin sensitivity and heart functions improved.

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