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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Scientists find new target for Parkinson’s disease

Contrary to earlier discovery that a chemical found in a synthetic opioid, MPTP, induced a form of Parkinson’s disease, a new study has found that it is an enzyme in the body that can metabolise compounds formed in the brain from alkaloids causing a neurodegenerative condition in mice.

The study led by Narayan Avadhani and Mrittika Chattopadhyay, suggested that the enzyme, mitochondrial CYP2D6, presents a potentially powerful new target for Parkinson’s treatment. “Over the past two or three decades, researchers have tried inhibiting the process by they believed MPTP was metabolised, with mixed success,” said Avadhani.

“We believe that mitochondrial CYP2D6 is the more direct drug target, which might prove better in treating idiopathic Parkinson’s disease,” added Avadhani. The study published in the ‘Journal of Biological Chemistry’ investigated the mechanism of Parkinson’s disease when a specific cause cannot be pinpointed. Previous studies have shown that MPTP and similar toxic compounds induce Parkinson’s disease in rodents and primates.

The mechanism of action, as scientists understood it, involved the compounds being oxidised to form MPP+, a toxic metabolite. The enzyme that was believed to be responsible is called monoamine oxidase B (MAO-B), present in the nervous system’s glial cells. In that conception of the mechanism, MPP+ was thought to then be transferred to dopamine neurons by dopamine transporter proteins, and, indeed, Parkinson’s is characterised by unusually low dopamine levels in the brain.

Researchers have tried to stem the effects of Parkinson’s by targeting two players in this presumed pathway, both MAO-B and the dopamine transporter protein, with only mixed success. In earlier work, Avadhani and colleagues had shown that the enzyme CYP2D6, localised to the body’s energy factories, the mitochondria, could play a role in metabolising MPTP to MPP+.

In the new investigation, they took a closer look at beta-carbolines and isoquinolines, toxins that resemble MPTP which the body produces from substances found in tobacco smoke, alcohol, and some foods. They found that, instead of MAO-B, it was mitochondrial CYP2D6 that activate the beta-carbolines and isoquinolines inside the dopamine-producing neurons, rather than the glial cells.

This route of activation, in a mouse model, results in neuronal damage and oxidative stress, symptoms akin to Parkinson’s. “CYP2D6 is known to play a role in influencing the activity of a number of drugs,” said Avadhani. In an attempt to target this pathway, the researchers showed that mice lacking CYP2D6 did not exhibit severe symptoms than mice with the protein did. In addition, an inhibitor of CYP2D6 prevented neuronal damage in the mice.

“The CYP2D6 inhibitor ajmalicine is a member of the reserpine family of alkaloids, found in the plant Rauwolfia serpentine and was long used in India for treating mental illness, such as paranoia and schizophrenia,” said Avadhani. “Mitochondrial targeting of such compounds is likely to be effective in treating Parkinson’s patients, and pursuing that is our future strategy,” said Avadhani.

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New molecular mechanism can reverse genetic defect responsible for Friedreich's ataxia

Scientists at Tufts University have identified a molecular mechanism that could reverse the genetic defect responsible for Friedreich's ataxia, a neurodegenerative disease that leaves its victims with difficulty walking, a loss of sensation in the arms and legs and impaired speech caused by degeneration of nerve tissue in the spinal cord.

The researchers report today in the Proceedings of the National Academy of Sciences that the genetic anomaly that causes the disease -- the multiple repetition of a three letter DNA sequence -- could potentially be reversed by enhancing a natural process that contracts the repetitive sequences in living tissue.

Friedreich's ataxia is a genetic disease caused by the presence of an expanded repetition of a three letter genetic sequence, GAA in the FXN gene, which encodes for frataxin, a protein required for proper function of the mitochondria -- the cell's "batteries" that generate the fuel to keep all other cell functions running.

Healthy people usually have 8 to 34 GAA repeats, carriers have 35 to 70 repeats, and individuals that exhibit disease symptoms have more than 70 -- and commonly have hundreds of repeats.

With more DNA repeats, it becomes increasingly difficult for the cells to "read" the FXN gene and produce the protein required by the mitochondria, which in turn cease to function properly. One in 40,000 individuals has this condition.

The DNA repeats literally gum up the works. They can also cause other mutations in the surrounding DNA, or make chromosomes extremely fragile, breaking into pieces, or rearranging themselves. If we can shrink the DNA repetition in tissues to levels found in healthy people, we might be able to stabilize the DNA and reduce the effects of disease."
Sergei Mirkin, professor and chair, Department of Biology, School of Arts & Sciences, Tufts University

It is known that in patients' tissues, the GAA repeats are unstable and continuously expand and contract. Understanding the mechanism of GAA repeat expansion and contraction -- especially contraction -- is important to developing this strategy for battling the currently incurable disease.
Numerous theories have been advanced as to how the DNA repeats contract, although the precise details of the mechanism remained largely unknown.

In order to pinpoint the actual mechanism, the authors of the study developed an experimental system in yeast (Saccharormyces cerevisiae) to quantitatively measure the effects of different interventions on contractions of DNA repeats, and found that contractions happened usually during the process of DNA replication, in the course of what is referred to as "lagging strand synthesis."

When the two strands of DNA are copied, one strand is replicated in a continuous manner, while the other must be assembled from smaller pieces stitched together.

This is the lagging strand, so named because its more complex synthesis limits the rate at which the DNA can be copied.

The Tufts researchers found that the contraction of repeats depends on the ability of the DNA repeat to form an unusual triple-helical DNA structure along the laggin strand.

The normal structure of DNA is a double helix consisting of two strands winding around each other. A triple helix, in contrast, consists of three strands wrapped in a helical twist.

As the replication machinery moves across the lagging strand, it cannot easily bypass a triplex formed by the repeat.

When the replication machinery jumps over this triple helix hurdle, the copied DNA strand ends up with fewer GAA repeats.

"While these results were uncovered in a yeast model, they do provide us with a clue into the mechanism of DNA repeat instability in Friedreich's ataxia," said Alexandra Khristich, graduate student in Mirkin's lab and first author of the study.

"I hope that our discovery would become a starting point for the potential development of therapeutic strategies that tip the balance toward DNA repeat contraction in patient tissues."

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