Cancer cell (white) being attacked by T cells (red). The new technology could be used to reduce toxic side effects from T cell immunotherapies. | NIH Image Gallery/ CC BY-NC 2.0
Kole Roybal is the 2018 grand prize winner of the inaugural Sartorius & Science Prize for Regenerative Medicine & Cell Therapy, for developing a new class of T cell immunotherapies that can be fine-tuned to better help the immune system recognize cancer and initiate precise therapeutic action against the disease. The findings, described in his prize-winning essay, " Refining cell therapy," could eventually help overcome the major hurdles that currently hinder T cell immunotherapies from reaching their full potential, and offer patients more favorable treatment outcomes.
Established in 2017, the Sartorius & Science Prize is an annual prize geared toward researchers focused on basic or translational research as described in a 1000-word essay that advances regenerative medicine and cell therapy (including cell-, gene-, or immunotherapy, tissue engineering, and materials engineering). The winner is awarded $25,000 and publication of his or her essay in Science.
For most available T cell immunotherapies, T cells (which play a central role in defending the body against illness) are engineered to recognize and eliminate tumors, but their activity is not specifically controlled, leading to toxicity and unwanted side effects in patients as a result of inflammation or in some cases suboptimal response to treatment. "If immune cell therapies for cancer or autoimmune diseases (like rheumatoid arthritis, for example) are going to be safe and effective alternatives to more traditional medications, we must gain control over the activity of the cells to reduce risks of toxicity to the patient," said Roybal.
To address such obstacles, Roybal, now an assistant professor at the University of California, San Francisco and his colleague Leonardo Morsut turned to a signaling molecule on T cells called the Notch receptor, known to be involved in several developmental and biological processes. Roybal reasoned that Notch could serve as a "sensor" able to detect disease or tissue-specific cues and initiate a more streamlined custom therapy. He developed "a la carte" synthetic Notch receptors (dubbed synNotch) that could be tailored towards a disease of interest, potentially bypassing harmful side effects and concentrating a treatment where it is needed the most.
In his award-winning essay, published in theMarch 9 issue of Science, Roybal highlights the benefits of the novel technology. "SynNotch receptors essentially allow us to confine the T cell response at the site of disease with the goal of enhancing the ability of the T cell to, for example, overcome the inhospitable microenvironment of a solid tumor. SynNotch engineered T cells are also versatile in that they can either be used drive a potent immune response to cancer or suppress an immune response in an autoimmune setting," he said.
"We can also program these T cells to perform functions that are non-natural. We have shown that T cells can locally produce commercial therapeutics (such as antibodies) in a solid tumor. In principle, we hope to engineer T cells or other cell types to reside in the body long-term and produce therapeutics if they recognize disease or recurrence of disease. This is very much akin to our natural immune system, which is always poised to respond to infection," said Roybal.
Killer T cells surround a cancer cell. | NIH Image Gallery / CC BY-NC 2.0
"Dr. Kole Roybal's research has used innovative technologies to rewire the immune system to recognize disease states," said Science Biomedicine Editor Priscilla Kelly. "He identified a type of molecular sensor, which programmed T cells isolated from human blood with customized instructions for thwarting attack. In principal, this synthetic switch could respond to cancer and autoimmune conditions, and possibly disorders of nerve and muscle cells. Dr. Roybal's work shows how cutting-edge science can deliver therapeutic opportunities for currently intractable diseases."
Roybal noted that his team is working intensely on developing synNotch T cells for clinical targets. Next steps will include engineering T cells that reliably detect multiple features on cancers such as mesothelioma and glioblastoma, allowing for more precise targeting of these diseases. He is also working on new receptor types that could allow cell therapies to more effectively penetrate disease sites and reside there for the duration of the treatment. "This could be especially useful for the treatment of solid tumors where T cell therapies have been largely ineffective," Roybal said.
"Science is pleased to partner with Sartorius to recognize leading work in the rapidly developing fields of regenerative medicine and cell therapy", said Science Editor-in-Chief Jeremy Berg, "These fields and the inaugural awardee review how decades of work on basic biological mechanisms might be harnessed to yield new therapies."
Roybal and the following finalists will be recognized during a ceremony that will take place March 20 in the Alte Mensa at the University of Goettingen, Germany:
Shruti Naik, for her essay "The healing power of painful memories." Naik received her B.S. in cell and molecular biology from the University of Maryland and her Ph.D. in immunology from the University of Pennsylvania-National Institutes of Health Graduate Partnership Program. During her graduate training, she discovered that normal bacteria living on our skin educate the immune system and help protect us from harmful pathogens, opening the door for microbiota-based therapies in the skin. She is currently at Rockefeller University, where she is studying the interactions between immune cells and stem cells in an effort to develop stem cell-based therapies for inflammatory disorders. She is also a strong advocate for women in science.
Fotios Sampaziotis, for his essay "Building better bile ducts." Sampaziotis graduated from the University of Athens in Greece with a degree in medicine. He obtained a Ph.D. in stem cell biology from the University of Cambridge. During his doctoral research, he pioneered the use of bile duct organoids to model diseases of the biliary system, test multiple drugs and identify new therapeutic agents. Fotios continues his research at the interface between basic science and clinical medicine as a clinical lecturer in hepatology at the University of Cambridge with clinical commitments in Addenbrooke's Hospital. His scientific work focuses on combining organoids, bioengineering and animal studies to regenerate damaged bile ducts in the liver as an alternative therapy to liver transplantation.
Will Mclean, for his essay "Towards a true cure for hearing impairment." As an undergraduate, McLean studied biology at Tufts University before going on to attain a Ph.D. at the Massachusetts Institute of Technology within the Harvard-MIT Division of Health Sciences and Technology. While at MIT, his doctoral research elucidated the distinct progenitor cell types that exist within the inner ear and their capacity to form sensory cells and neural cell types. As a postdoctoral researcher at Harvard Medical School, he investigated the use of small-molecule drugs to manipulate signaling pathways to enable otherwise senescent progenitor cells of the cochlea to divide and form new sensory cells. He is currently vice president of biology and regenerative medicine at Frequency Therapeutics, which is. using insights from McLean's previous work to develop a drug to treat hearing loss by regenerating lost sensory cells.
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