PERSPECTIVES IN HEALTH

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Breakthroughs in Medicine: Expert Q&As

Updated: Dec 11, 2020

Can we boost the immune system to fight cancer? What impact does COVID-19 have on patients' hearts? How is apathy related to our brain health? Dr. Kenneth Davis, President and CEO of Mount Sinai Health System, interviewed three experts- Dr. Steven Burakoff, Dr. Valentin Fuster, and Dr. Mary Sano- to discuss the latest research and innovations shaping the way we understand and treat cancer, heart disease, and Alzheimer's Disease.


Breakthroughs in Oncology: Q&A with Dr. Steven Burakoff

One of the most exciting breakthroughs in medicine is the harnessing of the immune system to fight cancer. Steven Burakoff, MD, is among the great innovators in this field. He is Dean for Cancer Innovation, Chief of Pediatric Oncology, and the Lillian and Henry M. Stratton Professor of Cancer Medicine at the Icahn School of Medicine at Mount Sinai.



Dr. Davis: Dr. Burakoff, where do we stand in the fight against cancer?


Dr. Burakoff: We are leading a national effort in developing cancer vaccines. This is an area that holds great promise. The challenge is, if you have cancer, can we boost your immune system to fight the cancer? The effort is early but promising.


In lung cancer, it turns out patients with preexisting lung cancer, about one-third, are responding to immunotherapy. We have 35 percent who are getting several years of response at this point. What we’re doing in immunotherapy is really cutting-edge.


Dr. Davis: Can you explain how you can create an effective vaccine?


Dr. Burakoff: To develop a vaccine you have to take the tumor and find out if there are molecules or antigens on the cell surface that are very much able to stimulate the immune system. This takes an enormous effort.


The tumor is sitting there and is not very immunogenic, but we are able to take apart the tumor. We then find the antigens of the tumor that stimulate the immune system and present them to the immune system in such a way that we can get the immune system to respond far better than normal.


Dr. Davis: Can you compare the hunt for cancer vaccines to the pursuit of vaccines for a virus?


Dr. Burakoff: The underlying effort of all vaccines is somewhat the same. Can you take a virus apart, can you take a tumor apart, find out which parts of them, when presented in the right way to the immune system, can provoke the immune system to respond better?


If you think about what’s happening with COVID-19, every one of those efforts is dedicated to finding what we can isolate in the virus to make them more immunogenic and make our immune system respond better to them. So, in the same way you’re doing this with the virus, we’re doing it with the tumor. In a tumor, it’s even more difficult because you have to look at thousands of components of the tumor.


Dr. Davis: How personalized is this experimental treatment?


Dr. Burakoff: Highly. Mount Sinai’s Director of Immunotherapy, Nina Bhardwaj, MD, PhD, and her team are sequencing patient tumors and identifying patients’ personalized neoantigens—new mutated antigens expressed by tumors.


We’ve developed prediction tools to identify which will be more immunogenic and recognized by the immune system. Using those prediction tools, we can come up with a ranking system. If a patient’s tumor has 100 mutations, we come up with a ranking: we pick the top 10 that are most likely to be immunogenic. We can synthesize those from the mutated region and compile it into a vaccine and then immunize patients with the goal of preventing regression or preventing tumor growth.


We’ve done it at Mount Sinai in three different trials, in glioblastomas (or brain tumors), in bladder cancer, and in melanoma.


At Mount Sinai we have set up an assembly line to rapidly sequence tumors, identify mutations, rank the mutations, synthesize potentially highly immunogenic mutations or peptides, formulate them into a vaccine, then deliver them to the patient. We hope we’ll get some sense of their efficacy next year.


Dr. Davis: That is highly personalized. How can we develop these sorts of vaccines on a large scale?


Dr. Burakoff: Yes. It’s very expensive. We have to make it for every patient. So, we’re working hard to find mutated antigens that are shared among patients. We’ve identified certain sets of tumors where mutations called frameshifts are shared among patients. That’s exciting because it means we could develop off-the-shelf vaccines for those patients that have these types of tumors.


The goal next year is to develop a new trial. We’ll test the hypothesis that the shared neoantigens would be immunogenic for many patients who have shared mutations.


We’re excited because we know the patients develop some immunity from these antigens but it’s not enough to work against the cancer, so we need to boost the immune response.


Dr. Davis: Do you see vaccines becoming a front-line treatment for cancer?


Dr. Burakoff: The data are still early, but clearly developing cancer vaccines is really what most people in the scientific community are seeing as the next generation of cancer treatments. We will use vaccines together with drugs that provoke the immune system.

If you go back historically to chemotherapy, the breakthrough was scientists ultimately found they had to use four drugs simultaneously to get cures in leukemia. I think there won’t be one size fits all. I think we will have an armamentarium of drugs for treatment. I think vaccines will be critical. They’ll be used in combination with other immunotherapy drugs.


Dr. Davis: What’s a realistic time frame for widespread use of cancer vaccines?


Dr. Burakoff: In the next five years cancer vaccines will be a critical component of cancer treatment.


What’s so exciting is, malignant melanoma was a cancer with a less than one-year survival rate 10 years ago. Then we came up with a drug that extended life. Then we came along with immunotherapy that now can get 40 percent of patients five years of survival.

You’re now seeing that with lung cancer. Metastatic lung cancer also had less than a one-year survival rate 10 years ago. Now you can get 30-40 percent of patients living anywhere from three to five years’ survival.


It’s a very exciting time. We’re deeply into these therapies because we have one of the largest cancer programs. We see 14,000 new cancer patients a year, so we have a grave responsibility to help these patients.


This is really just the beginning. The ultimate goal is to use a combination of treatments so that we can ultimately cure the disease. Our immune system will be a major component in dealing with cancer. There is no doubt.

Breakthroughs in Cardiology: Q&A with Dr. Valentin Fuster


Valentin Fuster, MD, PhD, is one of the leading cardiologists in the world, is generating new insights into heart disease, and is exploring innovative treatments that will save lives and improve the quality of life for patients. He is Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.



Dr. Davis: Dr. Fuster, what are you and your team researching?


Dr. Fuster: We are very interested in the relationship between cardiovascular disease development and the cognitive function of the brain.


We are exploring different questions that lead to the concept that high cholesterol, diabetes, and high blood pressure not only affect the large coronary arteries to cause stroke, but also affect the cognitive function of the brain. We’re finding that the same risk factors that affect the large arteries of the body may affect the circulation in the brain.


Dr. Davis: How do we know this?


Dr. Fuster: We are using three advanced imaging technologies together: High-sensitivity MRI, positron emission tomography, and high-sensitivity ultrasound. The combination of all three is allowing us to identify the correlation between cardiovascular issues and brain function. This has been a collaboration with the National Center for Cardiovascular Investigation in Madrid.


When there is disease of these large arteries in patients who have conventional cardiovascular risk factors—cigarette smoking, diabetes, high blood pressure—the flow of blood in the brain decreases because the tiny arteries of the brain begin to be obstructed.


This decrease in the blood flow in the brain affects the activity of the neurons in the brain. And this correlates with a decrease in cognitive function. This is new, something we didn’t know before.


Dr. Davis: Mount Sinai, as you know, treated a deluge of COVID-19 patients in the spring. At first, it was considered a respiratory disease, but you quickly saw in our patients that COVID-19 impacted coronary health as well.


Dr. Fuster: Yes. We saw the muscle of the heart is affected in COVID-19. Our researchers found 36 percent of patients hospitalized with COVID-19 had elevated troponin levels, indicating heart injury. These patients had a three times higher risk of mortality than patients without myocardial injury. We will be studying the main etiology to determine whether this is a direct effect of the virus or an indirect effect from a cytokine storm or a procoagulant that causes a clot inside a blood vessel of the heart.


Dr. Davis: Many COVID-19 patients were treated with blood thinners. How effective was that treatment?


Dr. Fuster: Our analysis shows anticoagulation therapy significantly improves survival of hospitalized COVID-19 patients.


Unfortunately, for people who suffer heart damage from COVID-19, we expect it will probably reverberate over the patient’s life. Based on our experience with other severe viral illnesses that affect the heart we know this happens. What’s less clear is what percentage of patients will have long-term issues.


Atrial fibrillation does occur in the context of COVID-19 and the inflammation COVID-19 causes. Atrial fibrillation probably happens in between 5-10 percent of hospitalized patients with COVID-19. It portends a worse prognosis.


Dr. Davis: There is a promising new technique to resolve atrial fibrillation.


Dr. Fuster: Yes. Vivek Reddy, MD, at Mount Sinai is using new technologies.


What we normally do in an atrial fibrillation ablation is we take a catheter and, using heat or extreme cold, we cauterize around the veins, all the way around to electrically isolate the vein. So, the electric impulses—the erratic electrical signals—are sequestered.


The problem is this approach is tissue-indiscriminate. It ablates all the tissue it encounters. So, the esophagus, which sits behind the heart, can also get ablated or other tissues can be ablated. These are rare complications, but when they occur, they’re a big deal.

Pulsed field ablation is different because unlike thermal ablation, where you’re burning or freezing tissue, with pulsed field ablation what is involved is applying high intensity electrical fields which essentially punch holes in cell membranes and cause membrane contents to leak out.


Why is it interesting? Number one, it’s quick. But the really interesting thing about it is the amount of energy needed to ablate the heart tissue is less than other types of tissue. So, we can use pulsed field energy to ablate just the heart tissue without ablating other tissues like the esophagus.


We take the catheter, we create this electrical field for just a couple of seconds, and that does the ablation we want.


Dr. Davis: Please put this in perspective so we know how much of an advance this is.


Dr. Fuster: It’s enormous. I can’t overemphasize the importance of this. It’s one of the most important advances since the advent of ablation for treating atrial fibrillation. It’s a qualitative improvement in the safety of the procedure.


Safety and efficacy always go hand in hand. You can always do more ablation, but can you do it safely enough? You can be safer by not ablating enough. Pulsed field ablation changes this. All the safety concerns are greatly diminished so you can get better efficacy with a quicker procedure.


Dr. Davis: How long before this becomes standardized?


Dr. Fuster: As soon as first device gets approved. A large, randomized trial will be conducted. The trial will begin in December or January and Mount Sinai will be the lead center. There will be somewhere between 400-500 patients. It probably will take a year to enroll, a year for follow-up, and a year for FDA approval. So, about three years from now it should be approved.

Breakthroughs in Alzheimer's Disease: Q&A with Dr. Mary Sano


Mary Sano, PhD, is Director of Alzheimer’s Disease Research at the Icahn School of Medicine at Mount Sinai and Director of Research and Development at the James J. Peters VA Medical Center in the Bronx. A neuropsychologist by training, she has been deeply involved in designing and conducting clinical trials for Alzheimer’s disease.


Dr. Davis: There has been a tremendous amount of focus on amyloid plaque and tau tangles in Alzheimer’s disease research. We know that in Alzheimer’s patients abnormal levels of beta-amyloid protein clump together to create plaques between neurons that disrupt cell function. Yet a Food and Drug Administration Advisory Committee recently recommended against approval of a drug that reduces amyloid. Your reaction?


Dr. Sano: We all want new and better treatments, but we need to be sure they work and they are safe. The panel that reviewed aducanumab actually supported the statistical review by the FDA, which noted that the effect was only apparent in those who had a very specific genotype (Apolipoprotein E4). Those sample cases had a high rate of serious side effect, which not only changes the risk-benefit ratio, but could also be responsible for over-predicting a benefit. The point is we need to get this correct or we may put lots of people in danger.


Even though these drugs can wipe out the amyloid, and soon we’ll have drugs that can wipe out tau, we’re not seeing a change in the course of the disease so we need another way to treat the symptoms of the disease.


Dr. Davis: What might that be?


Dr. Sano: Addressing neurodegeneration might be an approach. Treating comorbid conditions may help.


We believe inflammatory processes may cause brain dysfunction. Oxidative stress, metabolic changes that occur with aging need to be targeted to reverse or slow down the deterioration. But we don’t have a good marker for oxidative stress.


Dr. Davis: Comorbidities can impact brain health?


Dr. Sano: If a patient is developing Alzheimer’s, the symptoms of Alzheimer’s might be apparent earlier if she has conditions that could already challenge the brain, such as diabetes. If you have diabetes, your performance on certain types of cognitive tests is likely to be lower. The same may be true for hypertension.


With disease, and aging, there can be a reduction in brain volume. This is highly associated with cognition. Some of this can happen more rapidly with certain health conditions.


Dr. Davis: How do we counteract this risk of degeneration?


Dr. Sano: Deterioration can be reduced by things such as physical activity. Good data suggest brain volume can stabilize with physical activity. We’re working with groups on physical activity to see if aerobic activity can help maintain cognition and reduce the decline you’d expect with early disease or aging. We’re in the developmental stages. It makes good, rational sense. I expect we will see some benefit.


There’s a growing belief that exercise doesn’t protect against Alzheimer’s, but it might have a cognitive stabilizing effect.


We know about neuroplasticity. There may be treatments that can make neurons more plastic. This may involve growing more neurons by exposing the mind to music or studying a new subject area. There is a lot of research looking at physical, social, and cognitive activity as potential ways to maintain the brain.


We have a small study in early Alzheimer’s patients to see if music can keep a person linguistically active, to protect the brain from deterioration.


Dr. Davis: Could there be a drug that will help?


Dr. Sano: We might be able to do this pharmacologically. We might be able to find an agent that can strengthen synapses at the level of cellular models. We still have a lot to do.


Dr. Davis: What is your research showing with regard to the psychology of cognitive decline?


Dr. Sano: We’ve always known there are behavioral and psychological impacts of Alzheimer’s and cognitive decline.


Most recently, we’ve looked at apathy. Apathy is also measured in depression but it’s actually a separate entity. We’ve had some evidence that apathy is highly associated with functional deterioration. Even at early stages of disease there is a loss of interest and loss of initiation even while a person may still be functioning well neurologically.


Dr. Davis: Does apathy point to a decline in the ability to perform activities of daily living?


Dr. Sano: We’ve been monitoring this. We published a paper a year and a half ago which showed apathy had a big effect on cognition and function. Apathy had a very big affect on activities of daily living. Now we’ve completed another analysis that shows apathy is persistent throughout the course of disease. It does impact all sorts of cognitive impairment and it can start at an early stage of cognitive decline.


Dr. Davis: So, is apathy an early warning sign for family members?


Dr. Sano: I think that’s true. People tend to say they’re depressed, but it might be a loss of motivation or something we call executive function which occurs in areas of the brain that may be affected by many things. If apathy, or loss of interest persists, it might be the right time to get evaluated.


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