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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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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