Updated on Jun 30, 2022 | Community, Research
From left: Theresa Lin and Sarah Simon, research assistants; Katherine Leaver, MD, Assistant Professor of Neurology, Icahn School of Medicine at Mount Sinai; Sonya Elango, genetic counselor; Susan Bressman, MD; Deborah Raymond, genetic counselor; and Rachel Saunders-Pullman, MD, MPH, MS, Associate Professor of Neurology, Icahn School of Medicine at Mount Sinai.
Physician-scientists from Mount Sinai Beth Israel and The Michael J. Fox Foundation highlighted new treatments and research in Parkinson’s disease during a “Thankfest” symposium and lunch in October. The event was held to recognize the valuable contributions of 60 special attendees—patients who volunteer to participate in clinical trials to advance understanding of Parkinson’s disease.
“Clinical trials are in a very exciting new phase of targeted treatments that include correcting specific genetic causes,” says Susan Bressman, MD, a renowned Parkinson’s disease clinician and researcher. Dr. Bressman is the Mirken Family Professor of Neurology and Director of the Movement Disorders Center.
“The only way we will know if these approaches work is by testing them in patients,” says Dr. Bressman. “The process depends on the altruism of patients, and they deserve giant kudos.”
Updated on Jun 30, 2022 | Research
From left, front row: Kurt A. Yaeger, MD, PGY-5; Travis R. Ladner, MD, PGY-4; Ian T. McNeill, MD, MS, Chief Resident; Emily Chapman, medical student; and Alejandro Carrasquilla, MD, PGY-3; middle row: Ernest J. Barthélemy, MD, MA, MPH, PGY-6; Joshua B. Bederson, MD; J Mocco, MD, MS; and Abhiraj Bhimani, MD, PGY-1; and back row: Trevor Hardigan, MD, PhD, PGY-2; Leslie Schlachter, PA-C; and Georgios Maragkos, MD, Pre-residency Fellow.
The Department of Neurosurgery at the Icahn School of Medicine at Mount Sinai received the first place award for most accepted abstracts by residents at the 2019 Congress of Neurological Surgeons (CNS) Annual Meeting, which took place in October in San Francisco.
The 77 accepted abstracts were featured as oral presentations and posters, covering a wide range of topics, including spinal surgery and trauma, intracerebral hemorrhage, skull base tumors, glioblastoma, pediatric epilepsy, and neurocritical care, as well as socioeconomic issues related to neurosurgical treatment. At the 2018 CNS meeting, the Department placed third, with 35 accepted abstracts.
“Our trainees are strongly supported to perform research by Neurosurgery Vice Chair and Residency Program Director J Mocco, MD, MS. They are extremely active in exploring ways to work with faculty to improve how we treat neurological diseases and conditions, and the number of accepted abstracts we had at this year’s CNS meeting is a testament to that,” says Joshua B. Bederson, MD, Leonard I. Malis, MD/Corinne and Joseph Graber Professor of Neurosurgery, and Chair of Neurosurgery, Mount Sinai Health System.
Updated on Jun 30, 2022 | Cancer, Featured, Research
A PET-CT scan indicates one patient’s partial response to the in situ vaccination after six months. as shown in pre-vaccine, left, and six months post-vaccine.
Researchers at the Icahn School of Medicine at Mount Sinai are pioneering two novel approaches to cancer immunotherapy that are promising for patients with non-Hodgkin lymphoma and other solid tumors, which have been stubbornly resistant to therapies such as checkpoint blockade.
One new approach is an in situ vaccination that worked so well in patients with advanced-stage lymphoma that it is now undergoing trials for breast cancer, as well as head and neck cancers. The other therapy captures the synergy of checkpoint blockade and stem cell transplantation in the form of a highly promising treatment known as immunotransplant. Joshua Brody, MD, Director of the Lymphoma Immunotherapy Program and Assistant Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai, is the lead investigator for both therapies.
The In Situ Vaccination
This vaccination approach involves injecting immune stimulants directly into a single tumor site, which “teaches” the immune system to recognize and destroy cancer cells at that site and throughout the body. “We’re teaching dendritic cells—the generals of the immune system army—to specifically recognize tumor antigens, which then instruct the T cells, the immune system’s soldiers, to go forth and kill the cancer cells while sparing non-cancer cells,” says Dr. Brody.
As reported in the April 2019 issue of Nature Medicine, this therapy involves several steps that begin with injection of a small molecule that calls the dendritic cells to action, followed by low-dose radiation to kill the tumor cells. These dying cells, in turn, release antigens into the immune system that are recognized by the dendritic cells and presented to the T cells as part of the “coaching” process.
The results were encouraging among a cohort of 11 patients with non-Hodgkin lymphoma. In earlier tests with lab mice, the vaccine was able to cure about 40 percent of lymphoma tumors, Dr. Brody says. When combined with checkpoint blockade, the cure rate nearly doubled. Dr. Brody reports that when testing the therapy in patients, “We saw some who had profound regressions of their entire tumor burden. After treating one site, tumors throughout the body melted away.”
The next step in the development of the vaccine began last spring when Mount Sinai began recruiting patients for a clinical trial that combines the vaccine therapy with checkpoint blockade—a widely used treatment that effectively removes the brakes from T cells so they are free to attack cancer cells. This trial will target lymphomas, as well as breast cancer and head and neck cancers.
Immunotransplant Therapy
While PD-1 blockade has been effective for some lymphoma patients, its ability to help those with non-Hodgkin lymphoma has been more challenging. Even anti-PD-1/anti-CTLA4 dual checkpoint blockade has yielded limited efficacy, perhaps due to insufficient T cell activation.
Recently, Dr. Brody and his team found that combining immunotherapy and stem cell transplantation may be beneficial. In this first-of-its-kind approach, reported in Cancer Discovery, the researchers were able to increase the cancer-killing immune response tenfold when tested in the lab, making it effective against not just non-Hodgkin lymphoma but also melanoma and lung cancer.
“In the lab, immunotransplant either prolonged survival greatly compared to immunotherapy alone or actually cured a significant portion of mice with melanoma and lung cancer,” Dr. Brody says.
Immunotransplant works through the principle of homeostatic proliferation: when T cells are put into an empty organism or body, they become activated and begin to wildly multiply. In immunotransplant, T cells are withdrawn from the blood through apheresis, clearing the way for their reintroduction as infused immune cells. As they proliferate, these reinvigorated T cells build the immune system back up, become activated, and enable checkpoint blockade to achieve its full cancer-fighting potential.
The fact that checkpoint blockade has become the standard of care for treating melanoma, kidney cancer, lung cancer, and other diseases underscores the promise of immunotransplant. “We’ve shown we can increase the power of checkpoint blockade immunotherapy to prolong survival and induce cures in aggressive cancers, and that means not just lymphomas but solid tumor types,” says Dr. Brody.
Updated on Jun 30, 2022 | Featured, Research
Icahn School of Medicine at Mount Sinai authors of the study included, from left: Ron Do, PhD, Assistant Professor, Genetics and Genomic Sciences; Girish Nadkarni, MD, Assistant Professor of Medicine (Nephrology); and Kumardeep Chaudhary, PhD, Senior Postdoctoral Fellow, Genetics and Genomic Sciences. Dr. Nadkarni and Dr. Do are Co-Directors of the BioMe Phenomics Center.
A genetic variation that is prevalent in people of African or Hispanic/Latino ancestry was significantly associated with heart failure in a study by researchers at the Icahn School of Medicine at Mount Sinai and the Perelman School of Medicine at the University of Pennsylvania. The study, published in December 2019 in JAMA: The Journal of the American Medical Association, found underdiagnosis of affected patients and made a strong argument for wider genetic screening of the potentially deadly mutation, researchers say.
The team reported a significant association between the variation, TTR V142I, and a serious heart disorder, hereditary transthyretin amyloid cardiomyopathy (hATTR-CM). The TTR V142I gene variant, previously known as TTR V122I, causes the liver to produce misformed molecules of the transthyretin protein. The protein forms clusters, called amyloids, that can deposit in tissues throughout the body, including the nerves, kidneys, and joints. When amyloids lodge in the heart, they cause hATTR-CM, in which the walls of the heart become thicker and stiffer—in the worst case leading to heart failure.
“Using clinical data linked to the genetic data at the BioMe™ Biobank of Mount Sinai, we found that up to 4 percent of African-Americans and 1 percent of Hispanic/Latino Americans carried this mutation,” says a corresponding author of the study, Girish Nadkarni, MD, Assistant Professor of Medicine (Nephrology), and Co-Director of the BioMe Phenomics Center in The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine. “They had a higher risk of heart failure compared to people who didn’t have this mutation, but strikingly, very few of them had been appropriately diagnosed.”
Patient Wilbert Gibson with Sumeet S. Mitter, MD, left, and Donna M. Mancini, MD, Professor of Medicine (Cardiology), and Population Health Science and Policy.
The association of the TTR V142I variant with the clinical diagnosis of heart failure was evaluated in 9,694 individuals of African and Hispanic/Latino ancestry, using health records linked to genetic data from the BioMe Biobank and the Penn Medicine Biobank. Among carriers of the TTR V142I variant, the rate of diagnosis with hATTR-CM was assessed. The findings indicated both high rates of underdiagnosis and prolonged time to the appropriate diagnosis, says senior author Ron Do, PhD, Assistant Professor of Genetics and Genomic Sciences, and Co-Director of the BioMe Phenomics Center. Only 11 percent of individuals with the genetic variant and heart failure had been diagnosed with hATTR-CM, with an average time to appropriate diagnosis of three years.
“Our hope is if we can find individuals with amyloid cardiomyopathy early through genetic screening, we can start them on therapy before a heart transplant becomes the only clinical solution,” says Sumeet S. Mitter, MD, Assistant Professor of Medicine (Cardiology), and a leader of the multidisciplinary Clinical Amyloid Program at the Icahn School of Medicine. “Early diagnosis is even more important, given recent advances in treatment for hATTR-CM.” Treatment was limited to supportive care until May 2019, when the U.S. Food and Drug Administration approved the breakthrough drug tafamidis, made by Pfizer. However, timely diagnosis is critical, since the therapy stops amyloids from depositing in tissues, but does not reverse the course of the disorder.
The experience of a Mount Sinai patient, Wilbert Gibson, is emblematic. Mr. Gibson, 63, began having worrisome symptoms in early 2019. “My weight shot up from about 170 to nearly 200 pounds.” he says. “My legs were swelling; I was having shortness of breath.” Mr. Gibson was diagnosed with cardiac amyloidosis and found to have the TTR V142I mutation. His heart failure was so advanced that he required a transplant. He received a new heart in June 2019 and says he feels restored and grateful. However, he echoes clinicians and researchers in calling for more awareness of the gene variant, its prevalence in some populations, and its association with heart failure. “People should know about this,” Mr. Gibson says.
Updated on Jun 30, 2022 | Featured, Research
Catherine Sinclair, MD, performed radiofrequency ablation at Mount Sinai West.
Mount Sinai has become one of the few health systems in the nation to offer a new minimally invasive procedure to treat noncancerous thyroid nodules. The procedure, called radiofrequency ablation (RFA), offers eligible patients a quicker recovery and minimal scarring, with preservation of surrounding healthy thyroid tissue.
Catherine Sinclair, MD, Associate Professor of Otolaryngology, Icahn School of Medicine at Mount Sinai, and Director of Head and Neck Surgery at Mount Sinai West, performed Mount Sinai’s first RFA procedures in August 2019. “I truly believe this procedure will change management and improve outcomes for a subset of patients with symptomatic, noncancerous thyroid nodules,” says Dr. Sinclair. Mount Sinai is also a leader in offering ethanol ablation, a similarly noninvasive procedure.
Thyroid nodules are masses composed of tissue or fluid, or both, that form in the thyroid, a butterfly-shaped gland near the front of the lower neck. Nodules are very common, estimated to be present in 50 percent of those aged 50 and older. More than 95 percent are noncancerous, and most require no intervention. “For noncancerous thyroid nodules, we intervene surgically or with RFA only if the nodules are very large or symptomatic,” Dr. Sinclair explains. “Symptoms may include neck discomfort, neck swelling, difficulty swallowing or breathing, or changes in the voice from pressure on the nerve to the larynx.”
Although invasive surgery is the most common management option, RFA is an important consideration for patients with noncancerous nodules, Dr. Sinclair says. With RFA, surgeons use guided ultrasound to deliver radiofrequency current to heat the thyroid nodule, which shrinks significantly over the next several months. Patients who undergo RFA can return to normal activity the next day and exercise normally within several days, compared with several weeks for patients who undergo standard thyroid surgery. In addition, RFA targets only the nodule, compared with traditional surgery, which usually removes one side of the thyroid and makes lifelong hormone supplements necessary for 20 to 30 percent of patients.
Catherine Sinclair, MD, left, and Maria Brito, MD.
“Radiofrequency ablation for thyroid nodules has been performed in Korea for over a decade and throughout Europe, and their outcomes are excellent. The published data show nodule shrinkage rates of more than 80 percent with RFA that is maintained over years of follow-up,” says Dr. Sinclair, who learned RFA from a pioneer in the field, Jung Hwan Baek, MD, PhD, at the Asan Medical Center in Seoul, South Korea.
Dr. Sinclair also has developed a continuous laryngeal reflex monitoring system that is used during RFA to prevent vocal cord damage and hoarseness, which are potential risks during both RFA and standard surgery. In the system, nerve fibers within the neck are continuously stimulated to check their function, allowing surgeons to quickly take preventive measures against injury. This innovative method does not require a neck incision and is the only monitoring technique available for noninvasive procedures such as RFA.
Mount Sinai is one of the few health systems in the region to offer ethanol ablation. In that procedure, an alcohol solution is injected into thyroid nodules, killing cells and causing the masses to slowly shrink. The procedure leaves only a small scar and is performed in the office with local anesthesia. Dr. Sinclair says ethanol ablation may be more effective than RFA for fluid-filled thyroid cysts, and RFA is a better noninvasive choice for large, solid nodules. A combination of both procedures can be used for cystic/solid lesions. Ethanol ablation is performed at the Mount Sinai Thyroid Center at Union Square by its Director, Maria Brito, MD, Assistant Professor of Medicine (Endocrinology, Diabetes and Bone Disease), Icahn School of Medicine; and Michael Via, MD, Associate Professor of Medicine (Endocrinology, Diabetes and Bone Disease), Icahn School of Medicine; and by Dr. Sinclair at Mount Sinai West.
“The procedures will not necessarily eliminate the nodule completely, and patients will still need to have ultrasound follow-ups to monitor the nodule,” Dr. Brito says. “But in appropriate cases, they are a terrific option. They make it very easy for
the patient.”
Updated on Jun 30, 2022 | Featured, Infectious Diseases, Research
Mount Sinai scientists, from left, Peter Palese, PhD; Florian Krammer, PhD, with a 3D model of the influenza virus hemagglutinin; and Adolfo García-Sastre, PhD.
The quest to develop a universal influenza vaccine that would be administered only once or twice in an individual’s lifetime and cover every strain of the virus moved closer to becoming a reality in October, when researchers at the Icahn School of Medicine at Mount Sinai showed that a novel method of protection against the influenza virus was safe and induced strong immune responses in humans.
The interim results of this phase 1 clinical trial—led by Mount Sinai scientists Florian Krammer, PhD; Peter Palese, PhD; and Adolfo García-Sastre, PhD—were published online in the October 17, 2019, issue of The Lancet Infectious Diseases.
Two types of proteins, hemagglutinin and neuraminidase, cover the surface of the influenza virus. Current influenza vaccines target the head of the hemagglutinin—a structure that changes often. Mount Sinai’s strategy, known as chimeric hemagglutinin (cHA), targets the stalk of the hemagglutinin, which is less variable.
In the Lancet Infectious Diseases study, the research team tested several cHA vaccine regimens in combination with an adjuvant, an ingredient that boosts the immune response to vaccines. All of the regimens induced antibody responses. But, “one vaccine regimen induced a broad antibody response after the first dose, and this response was not only cross-reactive for the currently circulating influenza virus but also to avian (bird) and bat influenza subtypes,” according to Dr. Krammer, Mount Sinai Professor of Vaccinology and Professor of Microbiology at the Icahn School of Medicine at Mount Sinai.
This, he says, showed that one vaccination might be enough to induce protection against changing seasonal influenza viruses and pandemic influenza viruses yet to arise. “The results indicate that we are moving toward a universal influenza vaccine, but these are still interim results.”
Dr. Palese, Horace W. Goldsmith Professor of Medicine, and Professor and Chair of the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, says the “ideal vaccine, given only once in a lifetime and protective against all influenza virus strains,” would go a long way in improving the health of millions of people in the United States and around the world.
A universal vaccine would overcome “antigenic drift,” the small changes in the genes of influenza viruses that render viruses different from one another and allow them to escape human immunity. This is the primary reason why influenza vaccines vary in effectiveness from one season to another and must be updated every year.
Still, influenza vaccines do offer protection from severe disease and physicians strongly recommend that patients get them annually. Despite their widespread availability, however, more than half of Americans were unvaccinated as of the beginning of December 2019, according to NORC at the University of Chicago, which conducts the National Immunization Survey for the U.S. Centers for Disease Control and Prevention (CDC).
Influenza remains deadly for some. The World Health Organization estimates that influenza-related respiratory illnesses account for between 290,000 and 650,000 deaths per year. Dr. Krammer says, “Developing new vaccines takes a lot of time and it’s hard to estimate how long it will take, but I firmly believe we will have a universal flu vaccine in our lifetime and probably sooner.”
In addition to Dr. García-Sastre, a co-senior researcher on the Lancet Infectious Diseases study, and the Irene and Dr. Arthur M. Fishberg Professor of Medicine, and Director of the Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, contributors included Cincinnati Children’s Hospital Medical Center; Duke University School of Medicine; the University of Chicago; and the nonprofit international health organization PATH. Funding was provided by a grant from the Bill & Melinda Gates Foundation.
