Examining the Effects of Immunotherapy on Cancer

Updated on Jun 30, 2022 | Cancer, Featured, Research

From left: Thomas Marron, MD, PhD; Adeeb Rahman, PhD, Associate Professor, Genetics and Genomic Sciences; and Miriam Merad, MD, PhD

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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Advancing the Study of Brain and Memory

Updated on Jun 30, 2022 | Featured, Research

Denise Cai, PhD

Denise Cai, PhD, Assistant Professor of Neuroscience, Icahn School of Medicine at Mount Sinai, is the recipient of a 2019 National Institutes of Health New Innovator Award to continue her novel research into the brain and memory.

The Award was established to accelerate the pace of biomedical, behavioral, and social science discoveries by supporting exceptionally creative early-career scientists with high-impact ideas. It provides Dr. Cai with $2.5 million in funding over five years.

Dr. Cai’s research is driven by two perplexing questions: How, precisely, does the brain optimize its capacity and efficiency to store memories? And, how do these processes change over time?  She and her research team will use a number of innovative approaches to further explore these concepts.

The effort includes the recording of neural activity in the brains of both younger and older study mice as they learn new spatial locations through a novel, wire-free miniature microscope known as the Miniscope system, which was co-developed with colleagues at the University of California, Los Angeles, and the Icahn School of Medicine. Using this new technology, the mice will wear tiny, head-mounted, wire-free microscopes as they enter a variety of different environments, enabling researchers to record and analyze thousands of neurons over the course of time.

“We will use a variety of techniques to observe and manipulate these populations of neurons to determine how the neural activity in the brain controls the animals’ behavior,” explains Dr. Cai. “Ultimately, we aim to learn how the brain optimizes its capacity to store information across a lifetime. I am tremendously grateful to have received the New Innovator Award, which will enable our lab to explore some fundamental, yet very complex, biological questions in the field of memory and cognition.”

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A Thank You to Clinical Trial Participants

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.”

First Place for Neurosurgery

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.

Novel Cancer Immunotherapies Show Promise

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.

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Gene Variant Is Strongly Linked to Heart Failure

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.

 

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